Furan and pyrrole containing lipoxygenase inhibiting compounds

ABSTRACT

Substituted furan and pyrrole compounds which are useful in inhibiting lipoxygenase enzymes, particularly 5-lipoxygenase.

TECHNICAL FIELD

This invention relates to organic compounds which inhibit lipoxygenaseenzymes. It also relates to methods and compositions for inhibitinglipoxygenase enzymes in human and animal hosts in need of suchtreatment.

BACKGROUND OF THE INVENTION

The lipoxygenases are a family of enzymes which catalyze the oxygenationof arachidonic acid. The enzyme 5-lipoxygenase converts arachidonic acidto 5-hydroperoxyeicosatetraenoic acid (5-HPETE). This is the first stepin the metabolic pathway yielding 5-hydroxyeicosatetraenoic acid(5-HETE) and the important class of mediators, the leukotrienes (LTs).

Similarly, 12- and 15-lipoxygenase, convert arachidonic acid to 12- and15-HPETE, respectively. Biochemical reduction of 12-HPETE leads to12-HETE, while 15-HPETE is the precursor of the class of biologicalagents known as the lipoxins.

A variety of biological effects are associated with these products fromlipoxygenase metabolism of arachidonic acid and they have beenimplicated as mediators in various disease states. For example, the LTsC4 and D4 are potent constrictors of human airways in vitro, and aerosoladministration of these substances to non-asthmatic volunteers inducesbroncho-constriction. LTB4 and 5-HETE are potent chemotactic factors forinflammatory cells such as polymorphonuclear leukocytes. They also havebeen found in the synovial fluid of rheumatoid arthritic patients.Leukotrienes have also been implicated as important mediators inallergic rhinitis, psoriasis, adult respiratory distress syndrome,Crohn's disease, inflammatory bowel disease, endotoxin shock, andischemia induced myocardial injury among others. The biological activityof the LTs has been reviewed by Lewis and Austen (J. Clinical Invest.73, 889, 1984 and by J. Sirois (Adv. Lipid Res. 21, 78, 1985).

The product 12-HETE has been found in high levels in epidermal tissue ofpatients with psoriasis. The lipoxins have recently been shown tostimulate elastase and superoxide ion release from neutrophils.

Thus, lipoxygenase enzymes are believed to play an important role in thebiosynthesis of mediators of asthma, allergy, arthritis, psoriasis, andinflammation. Blocking these enzymes interrupts the biochemical pathwaysbelieved to be involved in these disease states.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention there are 5- and/or12-lipoxygenase inhibiting compounds of the formula: ##STR1## wherein R₁is hydrogen, C₁ to C₄ alkyl, C₂ to C₄ alkenyl, or --NR₂ R₃, wherein R₂and R₃ are independently selected from hydrogen, C₁ to C₄ alkyl,hydroxyl, aryl or substituted aryl wherein substituents are selectedfrom halo, nitro, cyano, C₁ to C₁₂ alkyl, alkoxy, halosubstituted alkyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyland alkylsulfonyl; with the proviso that R₂ and R₃ are not bothhydroxyl;

X is oxygen, or NR₄ wherein R₄ is hydrogen, C₁ to C₆ alkyl, C₁ to C₆alkoyl, arylalkyl or aroyl;

A is selected from C₁ to C₆ alkylene and C₂ to C₆ alkenylene;

n is 0,1,2 or 3;

Y is selected independently- at each occurrence from hydrogen, halogen,hydroxy, cyano, halosubstituted alkyl, C₁ to C₁₂ alkyl, C₂ to C₁₂alkenyl, C₁ to C₁₂ alkoxy, C₃ to C₈ cycloalkyl, aryl, aryloxy, aroyl, C₁to C₁₂ arylalkyl, C₂ to C₁₂ arylalkenyl, C₁ to C₁₂ arylalkoxy, C₁ to C₁₂arylthioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, arylalkylamino,arylalkylaminocarbonyl, alkoxyalkoxyalkyl, alkoxyalkyl, arylalkoxyalkyl,arylathioalkoxyalkyl and substituted derivatives of aryl, aryloxy,aroyl, C₁ to C₁₂ arylalkyl, C₂ to C₁₂ arylalkenyl, C₁ to C₁₂ arylalkoxy,C₁ to C₁₂ arylthioalkoxy, arylalkoxyalkyl or arylthioalkoxyalkyl whereinsubstituents are selected from halo, nitro, cyano, C₁ to C₁₂ alkyl,alkoxy and halosubstituted alkyl;

and M is hydrogen, a pharmaceutically acceptable cation, aroyl, or C₁ toC₁₂ alkoyl.

The substituent(s) Y can be substituted at any of the positions on thearomatic ring.

Examples of compounds which are themselves within the scope of thepresent invention include, but are not limited to, the following:

N-hydroxy-N-(1-(5-methylfur-2-yl)ethyl) urea;

N-hydroxy-N-(1-(5-phenylfur-2-yl-)ethyl) urea;

N-hydroxy-N-(1-(5-phenylfur-2-yl)-ethyl)-N'-methyl urea;

N-hydroxy-N-(1-(5-phenylfur-2-yl)ethyl) acetamide;

N-hydroxy-N-(1-(5-(2-phenylethenyl)fur-2-yl)ethyl) urea;

N-hydroxy-N-(1-(5-(2-phenylethenyl)fur-2-yl)ethyl) N'-methyl urea;

N-hydroxy-N-(1-fur-2-ylethyl) propionamide;

N-hydroxy-N-(1-(1-methyl-5-phenylpyrrol-2-yl)ethyl)-N'-methyl urea;

N-hydroxy-N-(3-fur-2-ylprop-2-enyl) urea;

N-hydroxy-N-fur-3-ylmethyl urea;

N-hydroxy-N-(fur-3-ylmethyl)-N'-methyl urea;

N-hydroxy-N-(5-(2,4,6-trimethylphenyl)-fur-2-ylethyl) urea;

N-hydroxy-N-(1-(5-butylfur-2-yl)ethyl) urea;

N-hydroxy-N-(1-(5-phenylmethylfur-2-yl)ethyl) urea;

N-hydroxy-N-(1-(5-ethylfur-2-yl)ethyl)-methylpropionamide;

N-hydroxy-N-(1-(3,4-dimethylfur-2-yl)ethyl) propenamide;

N-hydroxy-N-(1-(3-methylfur-2-yl)ethyl) N',N'-dimethylurea;

N,N'-dihydroxy-N-(1-(5-methylfur-2-yl)ethyl) urea;

N-hydroxy-N-(2-fur-2-ylethyl) urea;

N-hydroxy-N-(1-methyl-1-fur-2-ylethyl) urea;

N-hydroxy-N-(pyrrol-2-ylmethyl) urea;

N-hydroxy-N-(5-methoxy-(1-fur-2-yl)ethyl) urea;

N-hydroxy-N-(5-fluoro-(1-fur-2-yl)ethyl) urea;

N-hydroxy-N-(3-trifluoromethyl-(1-fur-2-yl)ethyl) urea;

N-hydroxy-N-(5-phenylmethoxy-(1-fur-2-yl)ethyl) urea;

N-hydroxy-N-(4-benzoyl-(1-fur-2-yl)ethyl) urea;

N-hydroxy-N-(1-acetoxy-(1-pyrrol-2-yl)ethyl) urea;

N-hydroxy-N-(1-benzoyl-(1-pyrrol-2-yl)ethyl) urea;

N-hydroxy-N-(1-(5-(4-fluorophenylfur-2-yl)ethyl) urea;

N-hydroxy-N-(1-(5-(3,5-dimethoxyphenylmethylfur-2-yl)ethyl) urea;

N-hydroxy-N-(3-hydroxy-(1-fur-2-yl)ethyl) urea;

N-hydroxy-N-(1-(5-methylfur-2-yl)ethyl) urea sodium salt;

N-hydroxy-N-(1-(5-methylfur-2-yl)ethyl) urea ammonium salt;

N-hydroxy-N-(1-(5-methylfur-2-yl)ethyl) urea tetrabutylammonium salt;

N-butyroxy-N-(1-(5-methylfur-2-yl)ethyl) urea;

N-hydroxy-N-(1-fur 2-ylethyl) urea;

N-hydroxy-N-(5-methylfur-2-ylmethyl) urea;

N-hydroxy-N-(5-methylfur-2-yl)methyl-N'-methyl urea;

N-hydroxy-N-(1-(5-methylfur-2-yl)ethyl)-N'-phenyl urea;

N-hydroxy-N-(1-(5-methylfur-2-yl)ethyl)-N'-(4-carboethoxyphenyl) urea;

N-hydroxy-N-(1-(5-methylfur-2-yl)ethyl)-N'-(4-carboxamidophenyl) urea;

N-hydroxy-N-(1-(5-methylfur-2-yl)ethyl)-4-methylsulfonylbenzamide;

N-hydroxy-N-(1-(5-carbomethoxyfur-2-yl)ethyl) urea;

N-hydroxy-N-(1-(5-carboethoxyfur-2-yl)ethyl) urea;

N-hydroxy-N-(1-(5-N,N-diethylcarboxamidofur-2-yl)ethyl) urea;

N-hydroxy-N-(1-(5-N-benzylcarboxamidofur-2-yl)ethyl) urea;

N-hydroxy-N-(1-(5-methoxyethoxymethylfur-2-yl)ethyl) urea;

N-hydroxy-N-(1-(5-ethoxymethylfur-2-yl)methyl) urea;

N-hydroxy-N-(1-(5-benzyloxymethylfur-2-yl)ethyl) urea;

N-hydroxy-N-(1-(5-phenylfur-2-yl)methyl) urea;

N-hydroxy-N-(5-phenylfur-2-yl)methyl-N'-methyl urea;

N-hydroxy-N-(3-(fur-3-ylprop-2-enyl) urea;

N-hydroxy-N-(3-(5-phenylfur-2-yl))prop-2-enyl) urea;

N-hydroxy-N-(2,5-dimethylfur-3-ylmethyl) urea;

N-hydroxy-N-(1-(2,5-dimethyl)fur-3-yl)ethyl) urea;

N-hydroxy-N-(1-fur-3-yl)ethyl) urea;

N-hydroxy-N-(1-(5-pyrid-2-ylfur-2-yl)ethyl) urea;

N-hydroxy-N-(3-(5-methylfur-2-yl)prop-2-enyl) urea;

N-hydroxy-N-(fur-2-ylmethyl) urea; and

N-hydroxy-N-((1-methyl)-3-(5-methylfur-2-yl)prop-2-enyl) urea.

Preferred compounds of the invention include:

N-hydroxy-N-(1-(5-methylfur-2-yl)ethyl) urea;

N-hydroxy-N-(1-(5-phenylfur-2-yl)ethyl) urea;

N-hydroxy-N-(1-(5-phenylfur-2-yl)ethyl)-N'-methyl urea;

N-hydroxy-N-(1-(5-phenylfur-2-yl)ethyl) acetamide;

N-hydroxy-N-(1-(5-(2-phenylethenyl)fur-2-yl)ethyl) urea;

N-hydroxy-N-(1-(5-(2-phenylethenyl)fur-2-yl)ethyl)-N'-methyl urea;

N-hydroxy-N-(5-(2,4,6-trimethoxyphenyl)-fur-2ylethyl) urea;

N-hydroxy-N-(1-fur-2-ylethyl)urea;

N-hydroxy-N-(1-(5-carbomethoxyfur-2-yl)ethyl) urea;

N-hydroxy-N-(1-(5-benzyloxymethylfur-2-yl)ethyl) urea;

N-hydroxy-N-(5-phenylfur-2-ylmethyl) urea;

N-hydroxy-N-(3-fur-3-ylprop-2-enyl) urea

N-hydroxy-N-(3-(5-phenylfur-2-yl)prop-2-enyl) urea;

N-hydroxy-N-(1-(2,5-dimethylfur-3-yl)ethyl) urea;

N-hydroxy-N-(1-fur-3-ylethyl) urea;

N-hydroxy-N-(1-(5-pyrid-2-ylfur-2-yl)ethyl) urea;

N-hydroxy-N-3-(1-(5-methylfur-2-yl)propenyl) urea; and

N-hydroxy-N-((1-methyl)-3-(5-methylfur-2-yl)prop-2-enyl) urea.

Most preferred compounds of the invention include:

N-hydroxy-N-(1-(5-methylfur-2-yl)ethyl) urea;

N-hydroxy-N-(1-(5-phenylfur-2-yl)ethyl) urea;

N-hydroxy-N-(1-(5-phenylfur-2-yl)ethyl)-N'-methyl urea;

N-hydroxy-N-(1-(5 phenylfur-2-yl)ethyl) acetamide;

N-hydroxy-N-(1-(5-(2-phenylethenyl)fur-2-yl)ethyl) urea;

N-hydroxy-N-(1-(5-(2-phenylethenyl)fur-2-yl)ethyl)-N'-methyl urea;

N-hydroxy-N-(5-(2,4,6-trimethoxyphenyl)-fur-2-ylethyl) urea;

N-hydroxy-N-(1-(5-benzyloxymethylfur-2-yl-)ethyl) urea;

N-hydroxy-N-(5-phenylfur-2-ylmethyl) urea;

N-hydroxy-N-(3-fur-3-ylprop-2-enyl) urea

N-hydroxy-N-(3-(5-phenylfur-2-yl)prop-2-enyl) urea;

N-hydroxy-N-(1-fur-3-ylethyl) urea;

N-hydroxy-N-(1-(5-pyrid-2-ylfur-2-yl)ethyl) urea;

N-hydroxy-N-3-(1-(5-methylfur-2-yl)propenyl) urea; and

N-hydroxy-N-((1-methyl)-3-(5-methylfur-2-yl)prop-2-enyl) urea.

The term "alkylene" is used herein to mean straight or branched chainspacer radicals such as --CH₂ --, --CH(CH₃)--, --C(CH₃)₂ --, --CH(C₂H₅)--, --CH₂ CH₂ --, --CH₂ CH(CH₃)--, --C(CH₃)₂ C(CH₃)₂ --, --CH₂ CH₂CH₂ -- and the like.

The term "alkenylene" is used herein to mean straight or branched chainunsaturated spacer radicals wherein the unsaturation comprises acarbon-carbon double bond, such as --CH═CH--, --CH═CHCH₂ --,--CH═CHCH(CH₃)--, --C(CH₃)═CHCH₂ --, --CH₂ CH═CHCH₂ --, --C(CH₃)₂CH═CHC(CH₃)₂ --, and the like.

The term "alkyl" is used herein to mean straight or branched chainradicals of 1 to 12 carbon atoms, including, but not limited to methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl,and the like.

The term "alkenyl" is used herein to mean straight or branched chainunsaturated radicals of 2 to 12 carbon atoms, including, but not limitedto ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, and the like.

The term "cycloalkyl" is used herein to mean carbocyclic radicals,preferably of 3 to 8 carbons, including, but not limited to cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "alkoxy" is used herein to mean --OR₁₅ wherein R₁₅ is an alkylradical, including, but not limited to methoxy, ethoxy, isopropoxy,n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, and the like.

The term "alkoyl" is used herein to mean --COR₁₆ wherein R₁₆ is an alkylradical, including, but not limited to formyl, acetyl, propionyl,butyryl, isobutyryl, pivaloyl, and the like.

The term "alkoxycarbonyl" is used herein to mean --C(O)R₁₇ wherein R₁₇is an alkoxy radical, including, but not limited to carbomethoxy,carboethoxy, carboisopropoxy, carbobutoxy, carbosec-butoxy,carboisobutoxy, carbotert-butoxy, and the like.

The term "aryl" is used herein to mean substituted and unsubstitutedaromatic carbocyclic radicals and substituted and unsubstitutedheterocyclic aromatic radicals wherein the substituents are selectedfrom halo, nitro, cyano, C₁ to C₁₂ alkyl, alkoxy, halosubstituted alkyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyland alkylsulfonyl including, but not limited to, phenyl, 1-naphthyl or2-naphthyl, fluorenyl, pyridyl, quinolyl, thienyl, thiazolyl, pyrimidyl,indolyl and the like.

The term "heterocyclic aromatic" is used herein to refer to 5 and 6membered aromatic rings having in the ring one, two or three heteroatomsselected from N, O and S; and also including benzo fused analogs ofthese 5 and 6 membered heterocyclic aromatic rings including, but notlimited to, pyridyl, quinolyl, furyl, benzofuryl, thienyl-, thiazolyl,pyrimidyl, indolyl and the like.

The term "aroyl" is used herein to mean --C(O)R₁₈ wherein R₁₈ is an arylradical, including, but not limited to benzoyl, 1-naphthoyl,2-naphthoyl, and the like.

The term "aryloxy" is used herein to mean --OR₁₉ wherein R₁₉ is an arylradical, including, but not limited to phenoxy, 1-naphthoxy, 2-naphthoxyand the like.

The term "arylalkoxy" is used herein to mean --OR₂₀ wherein R₂₀ is anarylalkyl radical, including, but not limited to phenylmethoxy (i.e.,benzyloxy), 4- fluorobenzyloxy, 1-phenylethoxy, 2-phenylethoxy,diphenylmethoxy, 1-naphthyl-methyloxy, 2-napthylmethyloxy, 9-fluorenoxy,2-, 3- or 4-pyridylmethoxy, 2-, 3-, 4-, 5-, 6-, 7- , 8-quinolylmethoxyand the like.

The term "arylthioalkoxy" is used herein to mean --SR₂₁ wherein R₂₁ isan arylalkyl radical, including, but not limited to phenylthiomethoxy(i.e., thiobenzyloxy), 4- fluorothiobenzyloxy, 1-phenylthioethoxy,2-phenylthioethoxy, diphenylthiomethoxy, 1-naphthylthiomethoxy and thelike.

The term "arylalkyl" is used herein to mean an aryl group appended to analkyl radical, including, but not limited to phenylmethyl (benzyl),1-phenylethyl, 2-phenylethyl, 1-naphthylethyl and the like.

The term "arylalkenyl" is used herein to mean an aryl group appended toan alkenyl radical, including, but not limited to phenylethenyl,3-phenylprop-1-enyl, 3- phenylprop-2-enyl, 1-naphthylethenyl and thelike.

The terms "halo" and "halogen" are used herein to mean radicals derivedfrom the elements fluorine, chlorine, bromine, or iodine.

The term "halosubstituted alkyl" refers to an alkyl radical as describedabove substituted with one or more halogens including, but not limitedto, chloromethyl, trifluoromethyl, 2,2,2-trichloroethyl, and the like.

The term "arylalkoxycarbonyl" is used herein to refer to R₂₂ C(O)--wherein R₂₂ is an arylalkoxy group.

The term "aminocarbonyl" is used herein to refer to --C(O)NH₂.

The term "alkylaminocarbonyl" is used herein to refer to --C(O)NHR₂₃wherein R₂₃ is an alkyl group.

The term "dialkylaminocarbonyl" is used herein to refer to --C(O)NR₂₄R₂₅ wherein R₂₄ and R₂₅ are independently selected from alkyl.

The term "arylalkylamino" as used herein refers to R₂₆ NH-- wherein R₂₆is an arylalkyl group.

The term "alkoxyalkoxyalkyl" is used herein to refer to an alkoxy groupappended to an alkoxy group which is itself appended to an alkyl radicalincluding, but not limited to methoxyethoxymethyl, ethoxyethoxymethyland the like.

The term "alkoxyalkyl" is used herein to refer to an alkoxy groupappended to an alkyl radical including, but not limited to,methoxymethyl, ethoxymethyl and the like.

The term "arylalkoxyalkyl" is used herein to refer to an arylalkoxygroup appended to an alkyl radical including, but not limited to,benzyloxymethyl, naphthylmethyloxymethyl and the like.

The term "alkylsulfonyl" is used herein refers to R₂₇ SO₂ -- wherein R₂₇is an alkyl group.

The term "arylalkylaminocarbonyl" is used herein to refer to R₂₈ C(O)--wherein R₂₈ is an arylalkylamino group.

The term "pharmaceutically acceptable cation" refers to non-toxiccations including but not limited to cations based on the alkali andalkaline earth metals, such as sodium, lithium, potassium, magnesium,and the like, as well as nontoxic ammonium, quaternary ammonium, andamine cations, including, but not limited to ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, ethylamine, and the like.

The term "lipoxygenase" is used herein to mean 5- and/or12-lipoxygenase.

The compounds of the invention inhibit lipoxygenase, which makes thecompounds useful in the treatment and prevention of disease stateswherein lipoxygenase may be involved, including, but not limited to,asthma, rheumatoid arthritis, gout, psoriasis, allergic rhinitis, adultrespiratory distress syndrome, Crohn's disease, endotoxin shock,inflammatory bowel disease and/or ischemia induced myocardial or braininjury.

Method of Treatment

This invention also provides a method of treatment for inhibiting 5-and/or 12-lipoxygenase activity in a human or lower animal host in needof such treatment which method comprises administration to the human orlower animal host of a compound of the invention in a therapeuticallyeffective amount to inhibit lipoxygenase activity in the host. Thisinvention also provides a method of treating asthma, rheumatoidarthritis, gout, psoriasis, allergic rhinitis, adult respiratorydistress syndrome, Crohn's disease, inflammatory bowel disease,endotoxin shock, and/or ischemia-induced myocardial injury in a human orlower animal in need of such treatment comprising administering to thehuman or lower animal a therapeutically effective amount of a compounddescribed above. Further, this invention also provides a method oftreating or preventing the symptoms of the disease states mentionedabove.

The compounds of the present invention may be administered orally,parenterally or topically in dosage unit formulations containingconventional nontoxic pharmaceutically acceptable carriers, adjuvantsand vehicles as desired.

The term parenteral as used herein includes subcutaneous, intravenous,intraarterial injection or infusion techniques, without limitation. Theterm "topically" encompasses administration rectally and by inhalationspray, as well as by the more common routes of the skin and the mucousmembranes of the mouth and nose.

Total daily dose of the compounds of this invention administered to ahost in single or divided doses may be in amounts, for example, of fromabout 0.001 to about 100 mg/kg body weight daily and more usually 0.01to 10 mg/kg/day. Dosage unit compositions may contain such amounts ofsuch submultiples thereof as may be used to make up the daily dose. Itwill be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including thebody weight, general health, sex, diet, time and route ofadministration, rates of absorption and excretion, combination withother drugs and the severity of the particular disease being treated.

Formulation of Pharmaceutical Composition

This invention also provides for compositions in unit dosage form forthe inhibition of 5- or 12-lipoxygenase activity in a human or loweranimal host in need of such treatment, comprising a compound of thisinvention and one or more nontoxic pharmaceutically acceptable carriers,adjuvants or vehicles. The amount of active ingredient that may becombined with such materials to produce a single dosage form will varydepending upon various factors, as indicated above.

A variety of materials can be used as carriers, adjuvants and vehiclesin the composition of this invention, as available in the pharmaceuticalarts. Injectable preparations, such as oleaginous solutions, suspensionsor emulsions, may be formulated according to known art, using suitabledispersing or wetting agents and suspending agents, as needed. Thesterile injectable preparation may employ a nontoxic parenterallyacceptable diluent or solvent as, for example, sterile nonpyrogenicwater or 1,3-butanediol. Among the other acceptable vehicles andsolvents that may be employed are 5% dextrose injection, Ringer'sinjection and isotonic sodium chloride injection (as described in theUSP/NF). In addition, sterile, fixed oils are conventionally employed assolvents or suspending media. For this purpose any bland fixed oil maybe used, including synthetic mono-, di- or triglycerides. Fatty acidssuch as oleic acid can also be used in the preparation of injectablecompositions.

Suppositories for rectal administration of the compound of thisinvention can be prepared by mixing the drug with suitable nonirritatingexcipient such as cocoa butter and polyethylene glycols, which are solidat ordinary temperatures but liquid at body temperature and whichtherefore melt in the rectum and release the drug.

Solid dosage forms for oral administration include capsules, tablets,pills, troches, lozenges, powders and granules. In such solid dosageforms, the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, pharmaceutical adjuvant substances,e.g., stearate lubricating agents. In the case of capsules, tablets andpills, the dosage forms may also comprise buffering agents. Solid oralpreparations can also be prepared with enteric or other coatings whichmodulate release of the active ingredients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirscontaining inert nontoxic diluents commonly used in the art, such aswater and alcohol. Such compositions may also comprise adjuvants, suchas wetting agents, emulsifying suspending, sweetening, flavoring andperfuming agents.

Synthesis of the Compounds

Several synthetic methods may be used to prepare compounds of thisinvention. Some of these methods are described by schemes 1-5 below.Although in each case the sequence is illustrated with a compound offormula I wherein R₁ is methyl or NH₂, A is --CH(CH₃)--, X is oxygen andY is hydrogen, it will be seen from the examples that other compounds ofthis invention can be prepared in the same manner using the appropriatestarting materials. Compounds of formula I wherein R₁ is CH₃ can beprepared as described in scheme 1. ##STR2##

In scheme 1, 2-acetylfuran 1 is treated with hydroxyl amine inethanol/pyridine to produce the oxime 2. This is reduced to thehydroxylamine 3 with borane pyridine complex and then converted to theN,O-diacetate 4 with acetyl chloride and triethylamine. The diacetate isconverted to the hydroxamic acid 5 by hydrolysis with lithium hydroxide.

Other reagents can also be used to carry out the same transformation.For example, 2 can be converted to 3 using borane trimethyl amine,borane-tetrahydrofuran, or other borane complexes. Intermediate 2 canalso be converted to 3 with sodium cyanoborohydride or withphenyldimethylsilane in trifluoroacetic acid. Hydroxylamine 3 can alsobe converted to 4 with acylating agents such as acetic anhydride in thepresence of other bases such as pyridine.

Compounds of formula I wherein R₁ is --NR₂ R₃ can be prepared accordingto the method outlined in scheme 2, below. ##STR3##

Hydroxylamine 3, the synthesis of which was described above, is treatedwith gaseous HCl followed by phosgene. The resulting putative carbamoylchloride 6 is reacted without isolation with aqueous ammonia to yieldthe urea 7.

Compounds of formula I, wherein R₁ is --NR₂ R₃ and wherein at least oneof either R₂ or R₃ is hydrogen can also be prepared according to Scheme3, below. ##STR4##

Hydroxylamine 3 is treated with trimethylsilyl isocyanate (TMSNCO),followed by ammonium chloride workup to give the urea 7. Alternatively,3 can be treated with sodium or potassium cyanate in an acidic solutionto yield the urea 7.

In addition to the methods described above, hydroxylamines such as 3 canbe prepared as shown in scheme 4, below. ##STR5##

Chloride 8 is treated with Z-furfuraldehyde oxime and a base such assodium methoxide to give nitrone 9. The nitrone is then hydrolyzed underacidic conditions or with hydroxylamine. The hydroxyl amine can beconverted to compounds such as 5 and 7 using the methodology describedabove. Compounds with other leaving groups such as bromides, iodides,tosylates, mesylates, triflates can be used instead of chloride 8.

In addition to the methods described above, compounds of this inventioncan also be prepared as described in scheme 5 below. ##STR6##

Chloride 8 is heated with O-benzylhydroxylamine in a solvent such asdimethylsulfoxide or tetrahydrofuran to yield the new hydroxylamine 10.This can either be reacted with acetyl chloride as in scheme 1 to yield11 or with trimethylsilyl isocyanate as in scheme 3 to yield 12.Compounds 11 and 10 are then hydrogenated to yield 5 and 7,respectively. Other O-protected hydroxylamines can also be used in placeof O-benzylhydroxylamine such as O- tetrahydropyranyl hydroxylamine.Further, other methods can be used to convert 10 to 7, such as treatmentwith phosgene followed by ammonium hydroxide such as described in scheme2, or treatment with sodium cyanate as described in scheme 3.

Compounds of this invention in which A is --CH₂ -- or --CH(alkyl)-- canalso be prepared as described in scheme 6. ##STR7##

Furan 13 is first converted to 2-lithiofuran by treatment withn-butyllithium. This is then treated with the O- benzyloxime ofacetaldehyde in the presence of BF₃ 3.Et₂ O to giveO-benzylhydroxylamine 10. This can be converted to the compounds such as5 or 7 as described in scheme 4. Other O- protected oximes can besubstituted for the O-benzyl oxime and other Lewis acids such as CeCl₃can be used. The following examples further illustrate the synthesis anduse of compounds of this invention. The appropriate designations for R₁,A, X and Y as defined by formula I are given for each example below.

Example 1 N-hydroxy-N-(1-(5-methylfur-2-yl)ethyl) urea

a. 2-Acetyl-5-methylfuran oxime. 2-Acetyl 5-methylfuran (5 g, 40.3mmole) and hydroxylamine hydrochloride (4.2 g, 60.4 mmole) weredissolved in a mixture of ethanol (20mL) and pyridine (6.5 mL) andheated at 50° C. for 2 hours. The reaction mixture was diluted withwater (300 mL) and extracted twice with ethyl acetate. The organic layerwas washed with 2N HCl and brine, dried over MgSO₄ and concentrated invacuo to provided 4.31 g of the desired product.

b. 1-(5-Methylfur-2-yl)ethyl hydroxylamine. The oxime prepared as instep b above (4.2q, 30 mmole) was dissolved in ethanol (200 mL) andcooled to 0° C. Borane pyridine complex (10 mL, 100 mmole) was added viasyringe under nitrogen followed one hour later by 6N HCl (100 mL).Within thirty minutes the reaction was complete and was brought to pH 9with the addition of 2N NaOH. The mixture was extracted into ethylacetate and dried over MgSO₄. After evaporation, the residue waschromatographed on 150 g silica gel, eluting with 60% ether in hexanesto obtained 1.8 g of a clear liquid.

c. N-Hydroxy-N-(1-(5-methylfur-2-yl)ethyl) urea. Using the method ofscheme 3, 1-(5-methylfur-2-yl)ethyl hydroxylamine prepared as describedabove in step b (1.8 g, 14.4 mmole), was refluxed for thirty minuteswith trimethylsilyl isocyanate (3.3 g, 28.8 mmole) in dioxane (40 mL).The reaction mixture was then washed with saturated NH₄ Cl solution. Theorganic layer was dried with MgSO₄, and evaporated. The residue waschromatographed on 75 g silica gel eluting with ethyl acetate to providethe desired product. (R1=--NH₂, A=2--(--CH(CH₃)--), X=O, Y=5-methyl)

Melting Point: 116°-118° C.

NMR (300 MHz, DMSO-d6): 1.32 (d, 3H, J=7.5 Hz); 2.21 (s, 3H); 5.25 (q,1H, J=7.5); 5.95 (m, 1H); 6.08 (m, 1H); 6.36 (br s, 2H); 8.90 (s, 1H).

IR (KBr): 3450, 3360, 3320, 2880, 1640, 1480.

Mass spectrum (CI-NH₃): 185 (M+1)⁺, 202 (M+NH₄)⁺.

Analysis (C₈ H₁₂ N₂ O₃): Calculated--C: 52.17, H: 6.57, N: 15.21; FoundC: 52.11, H: 6.61, N: 15.12.

Example 2 N-hydroxy-N-(1-(5-phenylfur-2-yl)ethyl) urea

a. 2-Phenyl furan. n Butyl lithium (60 mL, 2.5M in hexane) was added toa solution of furan (10.2 g, 1.5 mmole) in THF (100 mL). The mixture wasstirred for 3 hours at 0° C. and transferred via cannula to a stirredsuspension of zinc chloride (20.1 g, 150 mmole) in THF (100 mL). Themixture was stirred one hour and then a solution oftetrakis(triphenylphosphine) palladium 0.57 g, 0.5 mmole) intetrahydrofuran was added at room temperature. Bromobenzene (15.7 g, 100mmol) was then added and the temperature increased to 50° C. for 24hours. 0.1N HCL (100 mL) was added to the cooled solution followed byether (100 mL) The organic phase was washed with saturated sodiumcarbonate and brine, dried with MgSO₄ and evaporated. The residue wasdistilled (50°-55° C./0.6-0.9 torr) to give 12 g of the desired product.

b. 2-Acetyl-5-phenyl furan. n-Butyl lithium (33.6 mL, 2.5M in hexanes)was added dropwise to a solution of 2-phenylfuran, prepared as describedin step a, above, (12 g, 83.2 mmole). After being stirred for 30 minutesN,O- dimethylacetohydroxamic acid was added and allowed to stir at --20°C. for 1 hour, then at room temperature for 2 hours. The reaction wasquenched with the addition of saturated ammonium chloride solution. Themixture was extracted with ether and the organic layer was washed withbrine and dried over MgSO₄. The solvent was removed in vacuo to yield15.2 g of the desired product.

c. N-Hydroxy-N-(1-(5-phenylfur-2-yl)ethyl) urea was prepared accordingto the method of example 1, except using 2-acetyl 5-phenyl furan insteadof 2-acetyl-5-methyl furan. (R1=--NH₂, A=2--(--CH(CH₃)--), X=O,Y=5-phenyl).

Melting Point: 133°-136° C.

NMR (300 MHz, DMSO-d6): 1.41 (d, 3H, J=6.9Hz); 5.38 (q, 1H, J=6.9 Hz);6.35 (dd, 1H, J=1,3.3Hz); 6.48 (s, 2H); 6.85 (d, 1H); 7.22-7.45 (m, 3H);7.62-7.68 (m, 2H); 9.11 (s, 1H).

IR (CDCl₃): 3450, 3440, 1570, 1425, 1650.

Mass spectrum (CI-NH₃): 247 (M+1)⁺, 264 (M+NH₄)⁺, 171.

Analysis (C₁₃ H₁₄ N₂ O₃): Calculated--C: 63.40, H: 5.73, N: 11.38; FoundC: 62.82, H: 5.79, N: 11.22.

Example 3 N-hydroxy-N-(1-(5-phenylfur-2-yl)ethyl)-N'-methyl urea

The desired material was prepared according to the method of example 2,except using methyl isocyanate instead of trimethylsilyl isocyanate.(R1=--NHCH₃, A=2--(--CH(CH₃)--), X=O, Y=5-phenyl).

Melting Point: 120°-123° C.

NMR (300 MHz, DMSO-d6): 1.41 (d, 3H, J =6.6 Hz); 2.66 (d, 3H, J=3.9 Hz);5.35 (q, 1H, J =6.6 Hz), 6.33 (dd, 1H, J=1, 3.3 Hz); 6.84 (d, 1H, J=3.3Hz); 7.01 (q, 1H); 7.27 (m, 1H); 7.37-7.45 (m, 2H); 7.6-7.65 (m, 2H);9.03 (s, 1H).

IR (CDCl₃): 3535, 3455, 1660, 1530.

Mass spectrum (CI-NH₃): 261 (M+1)⁺, 278 (M+NH₄)⁺, 171.

Analysis (C₁₄ H₁₆ N₂ O₃): Calculated--C: 64.60, H: 6.20, N: 10.76; FoundC: 64.18, H: 6.19, N: 10.80.

Example 4 N-hydroxy-N-(1-(5-phenylfur-2-yl)ethyl) acetamide

a. N-Acetoxy-N-(1-(5-phenylfur-2-yl)ethyl) acetamide.1-(5-Phenylfur-2-yl)ethyl hydroxylamine (2.75 g, 13.5mmole) prepared asin example 1 above and triethyl amine (4.7 g, 33.7 mmole) were dissolvedin CH₂ Cl₂ and acetyl chloride (2.2 mL, 29.7 mmole) was added. Themixture was stirred for thirty minutes and poured into 2N HCl. Theorganic layer was dried over CH₂ Cl₂ and evaporated. The residue wascarried on without purification.

b. N-Hydroxy-N-(1-(5-phenylfur-2-yl)ethyl) acetamide. The materialprepared as described in step a above (3.8 g, 13.5 mmole) was dissolvedin isopropanol (50 mL) and added to a solution of lithium hydroxide(2.26 g, 54 mmole) in water (25 mL). The mixture was stirred for 1 hourand then partitioned between 1N HCl and ether. The organic phase wasdried over MgSO₄ and concentrated in vacuo. The residue wasrecrystallized from ether to give 2.026 g of the desired material.(R1=--CH₃, A=2--(--CH(CH₃)--), X=O, Y=5-phenyl).

Melting Point: 136° C.

NMR (300 MHz, DMSO-d6): 1.46 (d, 3H, J=6.6 Hz); 2.05 (s, 3H); 5.71 (q,1H, J=6.6 Hz); 6.42 (dd, 1H, J=1Hz, 3.3 Hz); 6.87 (d, 1H,); 7.27 (m,1H); 7.37-7.46 (m, 2H); 7.61-7.68 (m, 2H); 9.58 (s, 1H).

IR (CDCl₃): 2940, 2990, 1482, 1442, 1620.

Mass spectrum (CI-NH₃): 246 (M+1)⁺, 263 (M+NH₄)⁺, 171.

Analysis (C₁₄ H₁₅ NO₃): Calculated--C: 68.56, H: 6.16, N: 5.71; Found C:67.61, H: 6.29, N: 5.61.

Example 5 N-hydroxy-N-(1-(5-(2-phenylethenyl)fur-2-yl)ethyl) urea

a. 2-(2-Phenylethenyl) furan. n-Butyl lithium (16 mL, 2.5M in hexanes)was added to a solution of diethyl benzylphosphonate (9.2 g, 40.3 mmole)at -78° C. After being stirred for 15 min furfural (3.4 mL, 40.3 mmole)was added. The reaction was stirred for an additional 15 minutes at -78°C. and then at room temperature for 5 hours. Ammonium chloride solutionwas added to quench the reaction and the mixture was partitioned betweenether and water. The organic layer was dried over MgSO₄ andconcentrated. The residue was chromatographed on 500 g silica geleluting with CH₂ Cl₂ /pentane (1:10). A yield of 2.8 g of the desiredmaterial was obtained.

b. N-Hydroxy-N-(1-(5-(2-phenylethenyl)fur-2-yl)ethyl) urea. The desiredcompound was prepared using the method of example 2, except using the2-(2-phenylethenyl) furan instead of 2 phenylfuran. (R1=--NH₂,A=2--(--CH(CH₃)--), X=O, Y=5--(C₆ H₅ CH═CH--).

Melting Point: 140°_(]143)° C.

NMR (300 MHz, DMSO-d6): 1.60 (d, 3H, J =7.2 Hz); 5.35 (q, 1H, 7.2 Hz);6.32 (dd, 1H, J=1, 3.3 Hz); 6.46 (d, 1H; 3.3 Hz); 6.49 (s, 2H); 6.90 (d,1H, J=16.5 Hz); 7.07 (d, 1H, J =16.5 Hz); 7.2-7.4 (m, 3H); 7.5-7.6 (m,2H); 9.11 (s, 1H).

IR (CDCl₃): 3470, 1655, 1575, 1445.

Mass spectrum (CI-NH₃): 273 (M+1)⁺, 290 (M+NH₄)⁺, 197.

Analysis (C₁₅ H₁₆ N₂ O₃): Calculated--C: 66.16, H: 5.92, N: 10.92; FoundC: 64.90, H: 6.08, N: 9.68.

Example 6 N-hydroxy-N-(1-(5-(2-phenylethenyl)fur-2-yl)ethyl)-N'-methylurea

The desired compound was prepared according to the method of example 5,except using methyl isocyanate instead of trimethylsilyl- isocyanate.(R1=--NHCH₃, A=2--(--CH(CH₃)--), X=O, Y=5--(C₆ H₅ CH═CH--).

Melting Point: 156°-159° C.

NMR (300 MHz, DMSO-d6): 1.49 (d, 3H, J =6.9 Hz); 2.66 (d, 3H, J =3.6Hz); 5.82 (q, 1H, 6.9 Hz); 6.30 (dd, 1H, J =1, 3.3 Hz); 6.45 (d, H, J=3.3 Hz); 6.87 (d, 1H, J=16.5 Hz); 7.0-7.01 (m, 2H); 7.2-7.4 (m, 3H);7.5-7.6 (m, 2H); 9.04 (s, 1H).

IR (CDCl₃): 3450, 1665, 1530.

Mass spectrum (CI-NH₃): 287 (M+1)⁺, 304 (M+NH₄)⁺, 197.

Analysis (C₁₆ H₁₈ N₂ O₃): Calculated--C: 67.12, H: 6.34, N: 9.78; FoundC: 66.81, H: 6.50, N: 9.67.

Example 7 N-hydroxy-N-(1-fur-2-ylethyl) propionamide

The desired compound was prepared according to the method of example 4,except using 2-acetyl furan instead of 5- phenyl-2-acetyl furan. (R1=CH₃CH₂ --, A=2--(--CH(CH₃)--), X=O, Y=H).

Melting Point: 74°-76° C.

NMR (300 MHz, DMSO-d6): 0.99 (t, 3H); 1.40 (d, 3H); 2.38 (q, 2H); 5.65(q, 1H); 6.28 (m, 1H); 6.39 (m, 1H); 7.52 (m, 1H); 9.42 (br s, 1H).

Mass spectrum (CI-NH₃): 183 M+, 166, 110, 95.

Example 8 N-hydroxy-N-(1-(1-methyl-5-phenylpyrrol-2-yl)ethyl) N'- methylurea

a. 1-Methyl-2-phenyl pyrrole was prepared according to the method ofexample 2, step a, except using 1-methylpyrrole instead of furan

b. N-Benzyloxy-1-(1-methyl-5-phenylpyrrol-2-yl)ethylamine. t-Butyllithium (4.1 ml, 1.7M in hexanes) was added to a solution of the pyrroleprepared as in step a, above (1.0 g, 6.4 mmole) in THF (25 mL) at -78°C. After stirring for 30 minutes, boron trifluoride etherate (0.99 g,7.0 mmole) was added followed by O-benzyl acetaldehyde oxime (1.0 g, 7.0mmole). The mixture was stirred for 15 min, saturated NH₄ Cl solutionwas added, and the mixture was allowed to warm to room temperature. Theaqueous phase was washed twice with brine, dried over MgSO₄ andconcentrated. The residue was chromatographed on 100 g of silica geleluting with 20% ether in hexanes to give 0.34 g of the desired product.

c. N-benzyloxy-N-(1-(1-methyl-5-phenylpyrrol-2-yl)ethyl) N'-methyl ureawas prepared using the method of example 1, step c, except using thematerial prepared as in part b, above instead of1-(5-methylfur-2-yl)ethyl hydroxylamine, and using methyl isocyanateinstead of trimethylsilyl isocyanate.

d. N-hydroxy-N-(1-(1-methyl-5-phenylpyrrol-2-yl)ethyl) N'-methyl urea.The material prepared as in part c, above was dissolved in methanol andpalladium oxide on carbon (25 mg) added. The reaction mixture wasstirred under a positive atmosphere of hydrogen overnight. The mixturewas concentrated and the residue azeotroped with benzene to give thedesired product as a tan powder. (R1=--NH₂, A=2--(--CH(CH₃)--), X=NCH₃,Y=5-phenyl).

Melting Point: 158°-161° C.

NMR (300 MHz, DMSO-d6): 1.35 (d, 3H, J=7.5 Hz); 2.62 (d, 3 H, J=4.5 Hz);3.44 (s, 3H); 5.41 (m, 1H); 6.07 m, 2H); 6.87 (m, 1H); 7.30 (m, 1H);7.41 (m, 4H).

Mass spectrum (CI-NH₃): 274 (M+1)⁺, 258, 184, 158.

Example 9 N-hydroxy-N-(3-fur-2-ylprop-2-enyl) urea

The desired material was prepared according to the method of example 1,except using 3-fur-2-ylpropenal instead of 2-acetyl-5-methylfuran.(R1=--NH₂, A=2--(--CH═CHCH₂ --), X=O, Y=H).

Melting Point: 118°-121° C.

NMR (300 MHz, DMSO-d6): 4.06 (m, 2H); 6.06 (dt, 1H, J=16.5, 6 Hz); 6.41(m, 4H); 6.47 (m, 1H); 7.60 (m, 1H); 9.33 (s, 1H).

Mass spectrum (CI-NH₃): 183 (M+1)⁺, 200 (M+NH₄)⁺, 167, 107.

Analysis (C₈ H₁₀ N₂ O₃): Calculated--C: 52.74, H: 5.53, N: 15.38; FoundC: 52.51, H: 5.59, N: 1520.

Example 10 N-hydroxy-N-fur-3-ylmethyl urea

The desired compound was prepared according to the method of example 1,except using 3-furancarboxaldehyde instead of 2-acetyl-5-methyl furan.(R= --NH₂, A=3--(--CH₂ --), X=O, Y=H).

Melting Point: 125°-128° C.

NMR (300 MHz, DMSO-d6): 4.31 (s, 2H); 6.34 (brs, 2H); 6.40 (m, 1H); 7.56(m, 2H); 9.30 (s, 1H).

Mass spectrum (CI-NH₃): 157 (M+1)⁺, 174 (M+NH₄)⁺,

Analysis (C₆ H₈ N₂ O₃): Calculated--C: 46.15, H: 5.16, N: 17.94; FoundC: 45.80, H: 5.09, N: 17.72.

Example 11 N-hydroxy-N-fur-3 ylmethyl-N'-methyl urea

The desired compound was prepared according to the method of example 1,except using 3-furancarboxaldehyde instead of 2- acetyl-5-methyl furanand using methyl isocyanate instead of trimethylsilyl isocyanate.(R1=--NHCH₃, A=3--(--CH₂ --), X=O, Y=H).

Melting Point: 129°-131° C.

NMR (300 MHz, DMSO-d6): 2.58 (d, 3H, J=7.5 Hz); 4.30 (s, 2H); 6.39 (brs,2H); 6.90 (m, 1H); 7.55 (m, 2H); 9.22 (s, 1H).

Mass spectrum (CI-NH₃): 171 (M+1)⁺, 188 (M+NH₄)⁺,

Analysis (C₇ H₉ N₂ O₃): Calculated--C: 49.41, H: 5.92, N: 16.46; FoundC: 49.14, H: 5.97, N: 16.49.

Example 12 N-hydroxy-N-(5-(2,4,6-trimethylphenyl)-fur-2-ylethyl) urea

The desired compound was prepared according to the method of example 2,except using mesityl bromide instead of bromobenzene and using methylisocyanate instead of trimethylsilyl isocyanate. (R1=--NH₂,A=2--(--CH(CH₃)--), X=O, Y=5--(2,4,6-trimethylphenyl)).

Melting Point: 139°-141° C.

NMR (300 MHz, DMSO-d6): 1.40 (d, 3H, J=6.9 Hz); 2.13 (s, 6H); 2.25 (s,3H); 5.35 (q, 1H, 6.9 Hz); 6.28-6.32 (m, 2H); 6.39 (s, 2H); 6.91 (s,2H); 9.07 (s, 1H).

IR (CDCl₃): 3530, 2360, 2340, 1670, 1560.

Mass spectrum (CI-NH₃): 289 (M+1)⁺, 306 (M+NH₄)⁺, 213.

Analysis (C₁₆ H₂₀ N₂ O₃): Calculated--C: 66.65, H: 6.99, N: 9.72; FoundC: 6.64, H: 7.08, N: 9.72.

Example 13 N-hydroxy-N-(1-(5-butylfur-2-ylethyl) urea

The desired compound was prepared according to the method of example 2,steps b and c except using 2-butyl furan instead of 2-phenylfuran.(R1=--NH₂, A=2--(--CH(CH₃)--), X=O, Y=5-butyl).

Melting Point: 105°-107.5° C.

NMR (300 MHz, DMSO-d6): 0.89 (t, 3H); 1.32 (m, 5H); 1.53 (m, 2H); 5.74(m, 1H); 5.95 (m, 1H); 6.08 (m, 1H); 6.36 (br s, 2H); 8.97 (s, 1H).

Mass spectrum (CI-NH₃): 227 (M+1)⁺, 244(M+NH₄)⁺, 151.

Examples 14-31 are prepared in a manner generally analogous to thosedescribed in examples 1-13 and schemes 1-6.

Example 14 N-hydroxy-N-(1-(5-phenylmethylfur-2-yl)ethyl) urea

(R1=--NH₂, A=2--(--CH(CH₃)--), X=O, Y=5-benzyl)

Example 15 N-hydroxy-N-(1-(5-ethylfur-2-yl)ethyl) methylpropionamide

(R1=--CH(CH₃)₂, A=2--(--CH(CH₃)--), X=O, Y=5-ethyl)

Example 16 N-hydroxy-N-(1-(3,4-dimethylfur-2-yl)ethyl) propenamide

(R1=CH═CH₂, A=2--(--CH(CH₃)--), X=O, Y=3,4-dimethyl)

Example 17 N-hydroxy-N-(1-(3-methylfur-2-yl)ethyl)-N',N'-dimethylurea

(R1=--N(CH₃)₂, A=2--(--CH(CH₃)--), X=O, Y=3-methyl)

Example 18 N,N'-dihydroxy-N-(1-(5-methylfur-2-yl)ethyl) urea

(R1=--NHOH, A=2--(--CH(CH₃)--), X=O, Y=5-methyl)

Example 19 N-hydroxy-N-(2-fur-2-ylethyl) urea

(R1=--NH₂, A=2--(--CH₂ CH₂ --), X=O, Y=H)

Example 20 N-hydroxy-N-(1-methyl-1-fur-2-ylethyl) urea

(R1=--NH₂, A=2--(--CH₂ CH(CH₃)--), X=O, Y=H)

Example 21 N-hydroxy-N-pyrrol-2-ylmethyl urea

(R1=--NHCH₃, A=2--(--CH₂ --), X=NH, Y=H)

Example 22 N-hydroxy-N-(pyrrol-2-ylmethyl) urea

(R1=--NH₂, A=--CH₂ --, X=NH, Y=H

Example 23 N-hydroxy-N-(5-fluoro-(1-fur-2-yl)ethyl) urea

(R1=--NH₂, A=2--(--CH(CH₃)--), X=O, Y=5-fluoro)

Example 24 N-hydroxy-N-(3-trifluoromethyl-(1-fur-2-yl)ethyl) urea

(R1=--NH₂, A=2--(--CH(CH₃)--), X=O, Y=3-trifluoromethyl)

Example 25 N-hydroxy-N-(5-phenylmethoxy-(1 fur-2-yl)ethyl) urea

(R1=--NH₂, A=2--(--CH(CH₃)--), X=O, Y=5-benzyloxy)

Example 26 N-hydroxy-N-(4-benzoyl-(1-fur-2-yl)ethyl) urea

(R1=--NH₂, A=2--(--CH(CH₃)--), X=O, Y=4-benzoyl)

Example 27 N-hydroxy-N-(1-acetoxy-(1-pyrrol-2-yl)ethyl) urea

(R1=--NH₂, A=2--(--CH(CH₃)--), X=NCOCH₃, Y=H)

Example 28 N-hydroxy-N-(1-benzoyl-(1-pyrrol-2-yl)ethyl) urea

(R1=--NH₂, A=2--(--CH(CH₃)--), X=NCOC₆ H₅, Y=H)

Example 29 N-hydroxy-N-(1-(5-(4-fluorophenyl)-1-fur-2-yl)ethyl) urea

(R1=--NH₂, A=2--(--CH(CH₃)--), X=O, Y=5-(4-fluorophenyl))

Example 30 N-hydroxy-N-(1-(5-(3,5-dimethoxyphenylmethylfur-2-yl)ethyl)urea

(R1=--NH₂, A=2--(--CH(CH₃)--), X=O, Y=5-(3,5-dimethoxyphenylmethyl))

Example 31 N-hydroxy-N-(1-(3-hydroxyfur-2-yl)ethyl) urea

(R1=--NH₂, A=2--(--CH(CH₃)--), X=O, Y=3-hydroxy)

Example 32 N-hydroxy-N-(1-(5-methylfur-2-yl)ethyl) urea sodium salt

The material prepared as in example 1 is dissolved in tetrahydrofuranand one equivalent of sodium hydride is added. After hydrogen evolutionceases, hexane is added and the desired product collected by filtration.(R1=--NH₂, A=2--(--CH(CH₃)--), X=O, Y=5-methyl, M=Na).

Example 33 N-hydroxy-N-(1-(5-methylfur-2-yl)ethyl) urea ammonium salt

The material prepared as in example 1 is dissolved in tetrahydrofuranand ammonia is bubbled through the solution. Hexane is added and thedesired product collected by filtration. (R1=NH₂, A=2--(--CH(CH₃)--),X=O, Y=5-methyl, M=NH₄).

Example 34 N-hydroxy-N-(1-(5-methylfur-2-yl)ethyl) ureatetrabutylammonium salt

The material prepared as in example 1 is dissolved in tetrahydrofuranand one equivalent of tetrabutyl ammonium hydroxide is added. Hexane isadded and the desired product collected by filtration. (R1=--NH₂,A=2--(--CH(CH₃)--), X=O, Y=5-methyl, M=N(C₄ H₉)₄.

Example 35 N-butyroxy-N-(1-(5-methylfur-2-yl)ethyl) urea

The material prepared as in example 1 and 1.1 equivalents oftriethylamine are dissolved in tetrahydrofuran and 1 equivalent ofbutyryl chloride is added. Ether is added and the material is washedwith 2N HCl, dried with MgSO₄ and then evaporated to yield the desiredproduct. (R1=--NH₂, A=2--(--CH(CH₃)--), X=O, Y=5-methyl, M=COC₃ H₇).

Example 36 N-hydroxy-N-(1-fur-2-ylethyl) urea

a) To a solution of acetyl furan (25 g, 0.23 mol) in EtOH (40 mL) wasadded pyridine (37 mL, 0.45 mol) and hydroxylamine hydrochloride (24 g,0.34 mol) with stirring. The flask was heated to 50° C. for 1.5 hoursthen cooled to room temperature and diluted with 50 mL water and 30 mLethyl acetate. The aqueous layer was extracted with ethyl acetate (3×,20 mL). The combined organic extract was washed with 2M HC₁ (1×, 20 mL),brine (1×, 20 mL), dried over anhydrous MgSO₄, filtered and evaporatedto give the oxime intermediate (29 g).

b) The oxime (14 q, 0.11 mol) from the previous step was dissolved inEtOH (200 mL) and treated with borane-pyridine (34 mL, 0.34 mol). Thesolution was stirred 30 min at room temperature and then the flask wascooled to 0° C. and 6N HC₁ (366 mL) was added slowly. When the heat ofthe reaction had subsided the flask was warmed to room temperature andstirred until the reaction was complete. The solution was diluted withwater (100 mL) and the pH adjusted to 8-9 by the addition of solidsodium carbonate. The aqueous solution was extracted with ethyl acetate(3×100 mL) and the combined organic extract was washed with brine(1×150), dried over MgSO₄, filtered and concentrated to give an oil.Chromatography (silica gel, 60% ether in hexanes) gave the desiredhydroxylamine intermediate (8.5 g).

c) To a solution of trimethylsilylisocyanate (14 mL, 0.09 mol) in 100 mLtetrahydrofuran (THF) was added the oxime from part b) (5.5 g, 0.04 mol)in 25 mL THF. The reaction was warmed to reflux, stirred for 1 h, cooledto room temperature and diluted with saturated ammonium chloridesolution (50 mL). The aqueous layer was extracted with ethyl acetate(3×100 mL). The organic extract was with brine (100 mL), dried overMgSO₄, filtered and evaporated. The crude material was triturated withether and filtered. Recrystallization from ethyl acetate yielded thedesired product (4.2 g); m.p.=143°-144° C.; ¹ H NMR(300 MHz, DMSO-d6)9.04 (bs, 1H), 7.53 (m, 1H), 6.37 (m, 3H), 6.22 (m, 1H), 5.31 (q,J=5.40, 13.51 Hz, 1H), 1.33 (d, J=7.21 Hz, 3H); MS: (M+H)⁺ at 171;Analysis Calc'd for C₇ H₁₀ N₂ O₃ : C, 49.39; H, 5.93; N, 16.47. Found:C, 49.50; H, 6.04; N, 16.52.

Example 37 N-hydroxy-N-(5-methylfur-2-ylmethyl) urea

The desired material was prepared according to the method of Example 36,except using 5-methyl-2-furancarboxaldehyde instead of acetyl furan. Thedesired product was recrystallized from ethyl acetate and hexanes;mp=105° C.; ¹ H NMR (300 MHz, DMSO-d6): 9.33 (bs, 1H), 6.37 (bs, 2H),6.13 (d, J =3.02 Hz, 1H), 5.98 (m, 1H), 4.39 (bs, 2H), 2.21 (s, 3H); MS(M+H)⁺ =171.

Example 38 N-hydroxy-N-(5-methylfur-2-yl)methyl-N'-methyl urea

The desired material was prepared according to the method of Example 36,except using 5-methyl-2-furancarboxaldehyde instead of acetylfuran andmethylisocyanate instead of trimethylsilyl-isocyanate.

Example 39 N-hydroxy-N-(1-(5-methylfur-2-yl)ethyl)-N'-phenyl urea

To a solution of phenyl isocyanate (0.87 mL, 8.0 mmol) in 10 mL THF wasadded N-(1-(5-methyl-fur-2-yl)ethyl) hydroxylamine (0.50 g, 4.0 mmol) in3 mL THF. The reaction was stirred 1 h at room temperature and wasquenched with saturated ammonium chloride solution (25 mL). The aqueouslayer was extracted with ethyl acetate (3×10 mL) and the organic layerwas washed with brine (1×20 mL). The solution was dried with MgSO₄,filtered and evaporated. Chromatography (silica gel, 30% ether/hexanes)gave 0.32 g of desired product; m.p.=109°-110° C.; ¹ H NMR (300 MHz,DMSO-d6) 9.43 (bs, 1H), 8.97 (bs, 1H), 7.62 (dd, J=1.50, 8.71 Hz, 2H),7.25 (m, 2H), 6.96 (m, 1H), 6.15 (d, J=3.00 Hz, 1H), 5.38 (q, J=6.9,17.4 Hz, 1H), 2.19 (s, 3H), 1.39 (d, J=6.30 Hz, 3H); MS (M+H)⁺ =261;Analysis calc'd for C₁₄ H₁₆ N₂ O₃ : C, 64.59; H, 6.20; N, 10.77. Found:C, 64.00; H, 6.12; N, 10.60.

Example 40N-hydroxy-N-(1-(5-methylfur-2-yl)ethyl)-N'-(4-carboethoxyphenyl) urea

The desired material was prepared according to the method of Example 39,except using ethyl 4-isocyanatobenzoate instead of phenyl isocyanate.The product was chromatographed over silica gel with 60% ether/hexanesto yield a sticky white gum. ¹ H NMR (300 MHz, DMSO-d6) 9.57 (bs, 1H),9.37 (bs, 1H), 7.83 (m, 4H), 6.16 (d, J=2.85 Hz, 1H), 5.98 (m, 1H), 5.40(q, J=6.60, 14.41 Hz, 1H), 4.27 (q, J=6.60, 13.51 Hz, 2H), 2.09 (s, 3H),1.42 (d, J=6.60 Hz, 3H), 1.30 (t, J=6.33 Hz, 3H); MS (M+H)⁺ =333.

Example 41N-hydroxy-N-(1-(5-methylfur-2-yl)ethyl)-N'-(4-carboxamidophenyl) urea

To a solution of ammonium chloride (0.70 g, 13 mmol) in 75 mL of drymethylene chloride at -78° C. was added trimethylaluminum (13 mL, 26mmol; 2M solution in hexanes) via syringe. The solution was stirred 15min at -78° C. and was warmed to -20° C. for 30 min and then roomtemperature for 1 h. The solution was cooled to 0° C. andN-hydroxy-N-(1-(5-methyl-fur-2yl)ethyl) N'-(4- carboethoxyphenyl) urea(1.4 g, 4.3 mmol) in 20 mL of methylene chloride was slowly added. Thesolution was warmed to room temperature and then refluxed for 24 h. Whenthe mixture cooled to room temperature, 2.2 mL of 2M HCl was very slowlyadded and the solution was stirred 30 min, filtered and the solid wascollected. The solid was placed in 30 mL of 10% HCl solution and allowedto stir for 48 h and then filtered. The solid was then recrystallizedfrom ethanol/hexanes to yield 205 mg of product; m.p.=170°-171° C.; ¹ HNMR (300 MHz, DMSO-d6) 9.53 (bs, 1H), 9.22 (bs, 1H), 7.82 (bs, 1H), 7.77(m, 4H), 7.19 (bs, 1H), 6.16 (d, J=3.30 Hz, 1H), 5.97 (m, 1H), 5.40 (q,J=6.90, 13.81 Hz, 1H), 2.20 (s, 3H), 1.41 (d, J=6.60 Hz, 3H); MS (M+H)⁺=304; Analysis calc'd for C₁₅ H₁₇ N₃ O₄ : C, 59.38; H, 5.65; N, 13.86.Found: C, 58.88; H, 5.40; N, 13.53.

Example 42 N-hydroxy-N-(1-(5-methylfur-2-yl)ethyl)-4-methylsulfonylbenzamide

To a solution of 4-(methylsulfonyl) benzoic acid (3.1 g, 15.5 mmol) in100 mL of methylene chloride was added dimethylformamide (1.2 mL, 15.5mmol). The reaction vessel was cooled to 0° C. and oxalyl chloride (3.1mL, 35 mmol) was added. The mixture stirred 1 h at 0° C. and was addedto a solution of N-(1-(5-methyl-fur-2-yl)ethyl) hydroxylamine (2.6 g,18.6 mmol) and triethylamine (3.3 mL, 23.3 mmol) in 75 mL methylenechloride at 0° C. The mixture stirred 1.5 h and was poured into 2M HCl(100 mL). The aqueous layer was extracted with methylene chloride (3×,100 mL) and the combined organic extract was washed with saturatedsodium bicarbonate solution (1×100 mL) and brine (1×100 mL). Thesolution was dried over MgSO₄, filtered and evaporated. The material wasrecrystallized from ethyl acetate to yield 1.14 g of a white solid;m.p.=177° C.; ¹ H NMR (300 MHz, DMSO-d6) 9.85 (bs, 1H), 7.97 (d, J=8.41Hz, 2H), 7.83 (d, J=9.01 Hz, 2H), 6.24 (d, J=3.60 Hz, 1H), 6.02 (m, 1H),5.71 (bs, 1H), 3.26 (s, 3H), 2.24 (s, 3H), 1.47 (d, J=6.91 Hz, 3H). MS(M+H)⁺ =324; Analysis calc'd for C₁₅ H₁₇ NO₅ : C, 55.20; H, 5.25; N,4.29. Found: C, 55.07; H, 5.20; N, 4.23.

Example 43 N-hydroxy-N-(1-(5-carbomethoxyfur-2-yl)ethyl urea

a) To a solution of diisopropylamine (27.5 mL, 0.20 mol) in 200 mL ofTHF at 0° C. was added n-butyllithium (78.5 mL, 0.196 mol; 2.5M inhexanes). The solution was stirred 30 min and was cooled to -78° C. Asolution of furoic acid (10.0 g, 0.089 mol) in 100 mL of THF was addedand the solution stirred 30 min. To this mixture was added N-methoxy-N-methyl-acetamide (13.8 g, 0.134 mol) in 50 mL of THF. The reactionmixture was warmed to room temperature and stirred 1 h. The mixture wasquenched with saturated ammonium chloride solution and the aqueous layerwas washed with ether (3×50 mL) to remove impurities. The aqueous layerwas acidified with 2M HCl and extracted with ethyl acetate (3×100 mL).The combined organic extract was washed with brine, dried over MgSO₄,filtered and evaporated to yield 11.1 g (81%) of 2-acetyl-fur-5-ylcarboxylic acid.

b) A solution of 2-acetyl-fur-5-yl carboxylic acid (1.0 g, 6.49 mmol)was dissolved in 25 mL of methanol. HCl(g) was bubbled through thesolution until it was saturated. The methanol solution was then warmedto 60° C. and allowed to stir 45 min. The solution was concentrated to 5mL and then diluted with ether. The ether layer was washed withsaturated sodium bicarbonate solution and dried over MgSO₄, filtered andevaporated to yield 880 mg (81%) of 5-acetyl-2-methoxycarbonylfuran.

c) To a solution cf 2-acetyl-5-methoxy-carbonylfuran (0.88 g, 5.24 mmol)in 2.5 mL ethanol at room temperature was added pyridine (0.85 mL, 10.5mmol) and hydroxylamine hydrochloride (0.55 g, 7.86 mmol) with stirring.The reaction was complete after 1 h at room temperature. The solutionwas diluted with water and extracted with ethyl acetate (3×25 mL). Thecombined organic extract was washed with 2M HCl (30 mL), and brine (30mL) and dried over MgSO₄, filtered and concentrated to yield 1.09 g ofthe corresponding oxime intermediate.

d) The oxime of 2-acetyl-5-methoxycarbonylfuran (1.09 g, 5.95 mmol) wasdissolved in 5 mL ethanol at room temperature and borane-pyridine (1.8mL, 17.9 mmol) was added. The solution stirred 2 h at room temperatureand was cooled to 0° C. at which time 6N HCl (18 mL) was slowly added.When the heat of the reaction subsided, the flask was warmed to roomtemperature and allowed to stir approximately 4 h. The solution wasneutralized with solid sodium carbonate and diluted with ethyl acetateand water. The aqueous layer was extracted with ethyl acetate (3×50 mL)and the combined organic extract was washed with brine and dried overMgSO₄, filtered and evaporated. Chromatography on silica gel gave 368 mgof recovered oxime and 549 mg (50%) of the desired hydroxylamineintermediate.

e) To a solution of trimethylsilyl isocyanate (0.95 mL, 5.93 mmol) in 5mL THF at room temperature was added 1-(5-methoxycarbonylfur-2-yl)ethylhydroxylamine (0.549 mg, 2.97 mmol) in 10 mL of THF with stirring. After30 min the reaction was quenched with saturated ammonium chloridesolution (10 mL). The aqueous layer was saturated with NaCl andextracted with ethyl acetate (3×25 mL). The combined organic extract wasdried over MgSO₄, filtered and concentrated. Chromatography (silica gel,5% methanol/ether) yielded 500 mg (74%) of the desired product as asolid foam. The material was taken up in ethyl acetate, hexane was addedto the cloud point and the solution was placed in the freezer for anhour to yield white crystals; m.p.=99° C.; ¹ H NMR (300 MHz, DMSO-d6)9.18 (bs, 1H), 7.23 (d, J=3.90 Hz, 1H), 6.48 (m, 3H), 5.35 (q, J=12.61,6.30 Hz, 1H), 3.79 (s, 3H), 1.38 (d, J=7.20 Hz, 3H); MS (M+H)⁺ =229;Analysis calc'd for C₉ H₁₂ N₂ O₅ : C, 47.35; H, 5.30; N, 12.28. Found C,46.66; H, 5.26; N, 12.22.

Example 44 N-hydroxy-N-(1-(5-carboethoxyfur-2-yl)ethyl urea

The desired material was prepared according to the method of Example 43,except using ethanol in step b) instead of methanol; ¹ H NMR (300MHz,DMSO-d6) 9.18 (bs, 1H), 7.21 (d, J=3.75 Hz, 1H), 6.49 (bs, 2H), 6.46 (m,1H), 5.35 (q, J=7.26, 14.4 Hz, 1H), 4.27 (q, J=6.87, 13.81 Hz, 2H), 1.38(d, J=6.6 Hz, 3H), 1.27 (t, J=6.42 Hz, 3H); MS (M+NH₄)⁺ =260; Analysiscalc'd for C₁₀ H₁₄ N₂ O₅ : C, 49.57; H, 5.83; N, 11.57. Found: C, 48.71;H, 5.15; N, 10.98.

Example 45 N-hydroxy-N-(1-(5-N,N-diethylcarboxamidofur-2-yl)ethyl urea

a) To a solution of 2-acetyl-fur-5-yl carboxylic acid (0.50 g, 3.25mmol) in 5 mL of THF at 0° C. was added oxalyl chloride (0.30 mL, 3.41mmol) and N,N-dimethylformamide (25 mL, 0.33 mmol). The solution stirredat 0° C. for 1 h and then diethyl amine (0.67 ml, 0.71 mmol) in 5 mL ofTHF was added slowly. The solution was warmed to room temperature andallowed to stir overnight. The mixture was quenched with saturatedsodium bicarbonate solution and the aqueous layer was extracted withethyl acetate (3×15 mL). The combined organic extract was washed with10% HCl (1×20 mL) and brine (1×20 mL), dried over MgSO₄, filtered andconcentrated to yield 700 mg of 2-acetyl-fur-5-yl N,N-diethylcarboxyamide.

b) The desired product was prepared according to the method of Example43 starting at step c) using 2-acetyl-fur-5-yl N,N-diethylcarboxyamideinstead of 2-acetyl-5-methoxycarbonylfuran. No chromatography was neededto provide pure solid product; m.p.=139° C.; ¹ H NMR (300 MHz, DMSO-d6)9.15 (bs, 1H), 6.89 (d, J=3.45 Hz, 1H), 6.45 (bs, 2H), 6.35 (d, J=3.30Hz, 1H), 5.37 (q, J =6.90, 14.65 Hz, 1H), 3.45 (bs, 4H), 1.39 (d, J=6.30Hz, 3H), 1.16 (bs, 6H); MS (M+H)⁺ =270; Analysis calc'd for C₁₂ H₁₉ N₃O₄ : C, 53.50; H, 7.11; N, 15.61. Found: C, 53.05; H, 6.96; N, 15.27.

Example 46 N-hydroxy-N-(1-(5-N-benzylcarboxamidofur-2-yl)ethyl urea

The intermediate, 2-acetyl-fur-5-yl N-benzylcarboxyamide was preparedaccording to the method of Example 45 except benzylamine was usedinstead of diethylamine in step a). The desired product was preparedaccording to the method of Example 43 starting at step c) using2-acetyl-fur-5-yl N-benzylcarboxyamide instead of2-acetyl-5-methoxycarbonylfuran. The solid product was collected andwashed with ether; m.p.=169° C.; ¹ H NMR (300 MHz, DMSO-d6) 9.13 (bs,1H), 8.77 (t, J=5.25 Hz, 1H), 7.35-7.20 (m, 5H), 7.05 (d, J=3.02 Hz,1H), 6.49 (bs, 2H), 6.39 (m, 1H), 5.34 (q, J=6.90, 13.51 Hz, 1H), 4.41(d, J =6.15 Hz, 2H), 1.38 (d, J=6.45 Hz, 3H); MS (M+NH₄)⁺ =321; Analysiscalc'd for C₁₅ H₁₇ N₃ O.sub. 4 : C, 59.38; H, 5.65; N, 13.86; Found: C,58.89; H, 5.55; N, 13.58.

Example 47 N-hydroxy-N-(1-(5-methoxyethoxymethylfur-2-yl)ethyl) urea

a) To a solution of furan (10.7 mL, 0.147 mol) in 100 mL of THF at 0° C.was added n-butyllithium (65 mL, 0.149 mol). The reaction was stirred 3h and was cooled to -78° C. To the reaction flask was then slowly added2-methoxy-ethoxymethylchloride (16.8 mL, 0.147 mol) in 100 mL THF. Thesolution was warmed to -20° C. and allowed to stir until the solutionwas clear. It was then quenched with saturated ammonium chloridesolution (50mL) and the aqueous layer was washed with ethyl acetate (3×,50 mL). The combined organic layer was washed with brine, dried (MgSO₄),filtered and evaporated to yield 18 g of crude product. Distillationunder high vacuum yielded 14.5 g (63%) of 2-methoxyethoxy-methylfuran.

b) To a solution of diisopropylamine (9.9 mL, 70.5 mmol) in THF (30 mL)at 0° C. was added n-butyllithium (28 mL, 70.5 mmol, 2.5M in hexanes)and the solution was stirred 30 min and then cooled to -78° C. Asolution of the furan intermediate from part a). above (10 g, 64.1 mmol)in THF (30 mL) was added slowly. The mixture was stirred for 30 min. andthen N-methoxy-N-methylacetamide (9.9 g, 96.1 mmol) in THF (20 mL) wasadded. The solution was quenched with saturated ammonium chloridesolution (20mL) and the aqueous layer was extracted with ethyl acetate(3×, 20mL). The combined organics were washed with brine (1×, 20 mL),dried over MgSO₄, filtered and evaporated. Chromatography (silica gel,1:1 ether/hexanes) yielded (2.3 g) of the desired intermediate2-acetyl-5-methoxyethoxymethylfuran.

c) Following the procedure of example 36 using2-acetyl-5-methoxyethoxy-methylfuran instead of 2-acetylfuran thecorresponding oxime was prepared.

d) Following the procedure of example 36, part b). the oxime was reducedwith borane-pyridine to provide the corresponding hydroxylamineintermediate.

e) Following the procedure of example 36, part c). The desired productwas obtained. ¹ H NMR (300 MHz, DMSO-d6) 9.06 (bs, 1H), 6.41 (bs, 2H),6.31 (d, J=3.24 Hz, 1H), 6.18 (d, J=3.24 Hz, 1H), 5.29 (q, J=14.11, 6.84Hz, 1H), 4.34 (bs, 2H), 3.52 (m, 2H), 3.43 (m, 2H), 3.23 (s, 3H), 1.33(d, J=6.90 Hz, 3H). MS (M+H)⁺ =259, (M+NH₄)⁺ =276. Analysis calc'd forC₁₁ H₁₈ N₂ O₅ : C, 51.16; H, 7.02; N, 10.85. Found: C, 50.20; H, 6.41;N, 10.60.

Example 48 N-hydroxy-N-(1-(5-ethoxymethylfur-2-yl)methyl) urea

The title compound was prepared by the method of example 47, part a)using ethoxymethylchloride instead of 2-methoxy-ethoxymethylchloride.The final product was recrystallized from ether/hexanes. m.p.=80.5° C.;¹ H NMR (300 MHz, DMSO-d6) 9.49 (bs, 1H), 6.40 (bs, 2H), 6.32 (d, J=3.0Hz, 1, 6.21 (d, J=2.97 Hz, 1H), 4.45 (bs, 2h), 4.32 (bs, 2H), 3.44 (q,J=14.65, 7.20 Hz, 2H), 1.11 (t, J=6.30 Hz, 3H). MS (M+NH₄)⁺ =232.Analysis calc'd for C₉ H₁₄ N₂ O₄ : C, 50.44; H, 6.59; N, 13.08. Found:C, 50.37; H, 6.49; N, 13.02.

Example 49 N-hydroxy-N-(1-(5-benzyloxymethylfur-2-yl)ethyl) urea

The title compound was prepared by the method of example 47, part a)using chloromethylbenzylether instead of 2-methoxy-ethoxymethylchloride.The final product crystallized from ethyl acetate, was filtered andwashed with ether. m.p.=121° C.; ¹ H NMR (300 MHz, DMSO-d6) 9.06 (bs,1H), 7.38-7.27 (m, 5H), 6.42 (bs, 2H), 6.35 (d, J =3.02 Hz, 1H), 6.20(d, J=2.94 Hz, 1H), 5.30 (q, J =13.51, 6.91 Hz, 1H), 4.48 (bs, 2H), 4.40(bs, 2H), 1.35 (d, J=7.51 Hz, 3H); MS (M+NH₄)⁺ =308. Analysis calc'd forC15H18N2O4: C, 62.06; H, 6.25; N, 9.65. Found: C, 61.29; H, 6.26; N,9.50.

Example 50 N-hydroxy-N-(5-phenylfur-2-yl)methyl) urea

a) To a 0° C. solution of furan (10.2 g, 0.15 mol) in 100 mL of THF wasadded 2.5 M n-butyllithium (60 mL, 0.15 mol). The solution was stirred 3h and the suspension was then added to a solution of zinc chloride (20g, 0.15 mol) in 100 mL of THF at room temperature and stirred 1 h. Inanother flask bromobenzene (10.5 mL, 0.10 mol) was added to a solutionof tetrakis(triphenylphosphine)palladium(0) (0.57 g, catalytic) in 300ml THF and to this mixture was added the furyl zinc solution viacannula. The mixture was heated at 50° C. and stirred for 24 h. Thereaction was cooled and quenched with 10% aqueous HCl solution (100 mL).The aqueous layer was washed with ether (2×100 mL) and the combinedorganic extract was washed with saturated sodium bicarbonate solution(100 mL), brine (100 mL), dried over MgSO₄, filtered and concentrated.Distillation at 10 torr (b.p. 94° C.) yielded 12.1 g (81%) of2-phenylfuran.

b) To a 0° C. solution of N,N-dimethylformamide (1.9 mL, 24.97 mmol) ina three-neck flask equipped with a condenser was added POCl₃ (0.65 mL,6.94 mmol) dropwise via syringe with stirring. When the heat of thereaction subsided, 2-phenylfuran (1.0 g, 6.94 mmol) was added. Thereaction was warmed to 80° C. and stirred overnight. The solution wascooled to room temperature and then neutralized to pH 8 with aqueoussaturated sodium acetate. The mixture was extracted with ether (3×30mL), dried over MgSO₄, filtered and evaporated. Chromatography (silicagel, 20% ether/hexanes) yielded 1.0 g (83%) of 5-phenyl-2-furaldehyde.

c) Following the procedure of example 36 using 2-formyl-5-phenylfuraninstead of 2-acetylfuran the corresponding oxime was prepared.

d) Following the procedure of example 36, part b). the oxime was reducedwith borane pyridine to provide N-(5-phenylfur-2-yl)methylhydroxylamine.

e) Following the procedure of example 36, part c). the desired productwas obtained after chromatography (silica gel, ether). m.p.=149° C.; ¹ HNMR (300 MHz, DMSO-d6) 9.48 (bs, 1H), 7.66 (m, 2H), 7.41 (m, 2H), 7.26(m, 1H), 6.87 (d, J=3.15 Hz, 1H), 6.49 (bs, 2H), 6.39 (d, J=3.30 Hz,1H), 4.53 (bs, 2H); MS (M+H)⁺ =233, (M+NH₄)⁺ =250. Analysis calc'd forC₁₂ H₁₂ N₂ O₃ : C, 62.05; H, 5.21; N, 12.07. Found: C, 61.74; H, 5.14;N, 11.13.

Example 51 N-hydroxy-N-(5-phenylfur2-yl)methyl-N'-methyl urea

To a solution of N-(5-phenylfur-2-yl)methyl hydroxylamine (0.5 g, 2.64mmol) in tetrahydrofuran (30 mL) was added methylisocyanate (0.24 mL,3.97 mmol) dropwise at room temperature under nitrogen while stirring.The reaction was stirred for 20 h and ethyl ether (100 mL) and water(100 mL) was added. The organic layer was separated, washed withsaturated aqueous NaCl, dried over MgSO₄, filtered and concentrated invacuo, to give a solid (0.58 g). Purification by chromatography (silicagel, 2% methanol in dichloromethane) gave the desired product (0.28 g),mp 135°-139° C.; NMR (300 MHz, DMSO-d6): 2.63 (3H, d, J=5.4 Hz), 4.53(2H, s), 6.38 (1H, d, J=3.3 Hz), 6.87 (1H, d, J =3.3 Hz), 7.03 (1H, q,J=5.4 Hz), 7.24-7.30 (1H, m), 7.38-7.45 (2H, m), 7.38-7.45 (2H, m),7.62-7.68 (2H, m), 9.40 (1H, s); MS (CI-NH₃): M+H=247; AnalysisCalculated for C₁₃ H₁₄ N₂ O₃ : C, 63.40; H, 5.73, N, 11.38; Found C,63.29; H, 5.76; N, 11.34.

Example 52 N-hydroxy-N-(3-fur-3-yl-prop-2-enyl) urea

a) To a solution of 2N NaOH (115 mL) was added 3-furaldehyde (4.5 mL,52.0 mmol) dropwise. The solution was stirred until homogeneous(approximately five minutes) and then cooled to 0° C. and acetaldehyde(1.65 mL, 57.2 mmol) in 5 mL water was added. The reaction was stirredat 0° C. for 30 min and was then diluted with ether. The mixture wasseparated and the aqueous layer was extracted with ether (3×50 mL). Thecombined organic extract was washed with brine, dried over MgSO₄,filtered and evaporated to yield 4.56 g of crude product. Chromatography(silica gel ,30% ether/hexanes) yielded 2.6 g (41%) of3-(furan-3-yl)propenal.

b) Following the procedure of example 36 using 3-(furan-3-yl)propenalinstead of 2-acetylfuran the corresponding oxime was prepared.

c) The oxime was reduced following the procedure of example 36, part b).except the reaction was not warmed to room temperature after addition ofthe 6N HCl but instead the solution was stirred about 15 min at 0° C.and then neutralized to provide N-3-(1-fur-3-yl)propenyl hydroxylamine.

d) The desired product was prepared by following the procedure ofexample 36, part c) except the crude material was not chromatographedbut was diluted with ether/hexanes solution and filtered to give a paleyellow solid. m.p.=136°-137° C.; ¹ H NMR (300 MHz, DMSO-d6) 9.30 (bs,1H), 7.70 (bs, 1H), 7.61 (m, 1H), 6.70 (d, J=3.30 Hz, 1H), 6.42-6.32 (m,3H), 5.96 (m, 1H), 4.03 (m, 2H); MS (M+H)⁺ =183, (M+NH₄)⁺ =200. Analysiscalc'd for C₈ H₁₀ N₂ O₃ : C, 52.73; H, 5.54; N, 15.38. Found: C, 52.39;H, 5.55; N, 15.05.

Example 53 N-hydroxy-N-(3-(5-phenylfur-2-yl)prop-2-enyl) urea

a) The procedure of example 52 part a). was followed using5-phenyl-2-furaldehyde instead of 3-furaldehyde to provide5-phenyl-3-(furan-2-yl)propenal.

b) Following the procedure of example 36 using5-phenyl-3-(furan-2-yl)propenal instead of 2-acetylfuran thecorresponding oxime was prepared.

c) The oxime was reduced following the procedure of example 36, part b).except the reaction was not warmed to room temperature after addition ofthe 6N HCl but instead the solution was stirred about 15 min at 0° C.and then neutralized to provide N-3-(1-(5-phenylfur-2-yl))propenylhydroxylamine.

d) The desired product was prepared by following the procedure ofexample 36, part c). m.p. 157°-158° C.; ¹ H NMR (300 MHz, DMSO-d6) 9.48(bs, 1H), 7.73 (m, 2H), 7.43 (m, 2H), 7.29 (m, 1H), 6.97 (d, J=2.94 Hz,1H), 6.52 (d, J=3.02 Hz, 1H), 6.48-6.38 (m, 3H), 6.26-6.15 (m, 1H), 4.10(d, J=7.51 Hz, 2H); MS (M+H)⁺ =259. Analysis calc'd for C₁₄ H₁₄ N₂ O₃.65.09; H, 5.47; N, 10.85. Found: C, 63.48; H, 5.32; N, 10.07.

Example 54 N-Hydroxy-N-(2,5-dimethylfur-3-ylmethyl) urea

a) To a stirred solution of 3-carbomethoxy-2,5-dimethylfuran (2.5 g,16.2 mmol) in methylene chloride (distilled from CaH) at -20° C., underN₂, was added 2.5 eq of DIBAL (1M in CH₂ Cl₂). After 1 h, the dryice/acetonitrile bath was removed and 60 mL of 10% HCl was addeddropwise. The organic layer was separated, dried over MgSO₄, andevaporated. The residue was chromatographed (silica gel, 60%ether/hexane) to yield 1.3 g of 2,5-dimethyl-3- hydroxymethylfuran.

b) To a stirred solution of oxalyl chloride (11.3 mmol) in methylenechloride at -78° C. was added DMSO (20.6 mmol) dropwise. The mixture wasstirred for 10 min. then 2,5- dimethyl-3-hydroxymethylfuran (11.3 mmol)was added. The mixture was stirred for 30 min and then triethylamine (55mmol) was added slowly to the cold mixture. After 1 h the mixture wasfiltered , evaporated, diluted with THF, filtered again, and useddirectly in the next step.

c) Following the procedure of example 36 using 2,5-dimethylfuran-3-ylcarboxaldehyde instead of 2-acetylfuran thecorresponding oxime was prepared.

d) The oxime was reduced following the procedure of example 36, part b).except 10% HCl was used instead of 6N HCl to provideN-(2,5-dimethylfuran-3-yl)-methylhydroxylamine.

e) The desired product was prepared by following the procedure ofexample 36, part c),the residue was chromatographed (silica gel, 7%MeOH/CH₂ Cl₂) to yield 610 mg of the product. mp. 115°-117° C.;NMR(300MHz, DMSO-d6): 2.16 (6H, s); 4.17 (2H, s); 5.90 (1H, s); 6.26(2H, brs); 9.18 (1H, s); MS (CI-NH₃): M+H=185.

Example 55 N-Hydroxy-N-(1-(2,5-dimethylfur-3-yl)ethyl) urea

The title compound was prepared by the method of example 36 using3-acetyl-2,5-dimethylfuran instead 2-acetylfuran in an overall yield of15%. The product was recrystalyzed from EtOAc/Hex. m.p.=145°-146° C.;NMR (300MHz,DMSO-d6) 1.25 (3H,d, J=7.5Hz), 2.26 (6H,S), 5.09(1H,q,J=7.5Hz), 6.00 (1H,s), 6.23 (2H,br s), 8.95 (1H,s); MS (CI-NH₃):M+H=199

Example 56 N-Hydroxy-N-(1-fur-3-ylethyl) urea

a) To a stirred solution of 3-furaldehyde (5.6 g, 58 mmol) intetrahydrofuran (75 mL) at 0° C. was added a solution of CH₃ MgBr inether (64 mL. of 3M, 64 mmol). After 30 min saturated aqueous NH₄ Cl wasadded and the pH was adjusted to 7 with 10% aqueous HCl. The organiclayer was separated and the aqueous phase was extracted with ether. Thecombined organic layers were washed with brine, dried over MgSO₄,filtered and concentrated to give a yellow liquid (5.6 g) which was useddirectly in the next step.

b) To a solution of oxalyl chloride (7.3 g, 57 mmol) in dichloromethane(50 mL) at -78° C. was added DMSO (8.9 g, 114 mmol). The mixture wasstirred for 15 min. then a solution of the crude alcohol from part a).in dichloromethane (25 mL) was added dropwise. The reaction was stirredfor 30 min. at -78° C. and then triethylamine (26 g, 260 mmol) was addedto the reaction mixture and the mixture was allowed to warm slowly toroom temperature. The mixture was concentrated and the residue wastakenup in ether and filtered through a pad of Celite. The solids werewashed with ether and the combined ether filtrate was washed with water,brine, dried over MgSO₄, filtered and concentrated to give a solid (4.0g) which was purified by chromatography (silica gel, 1:1 ether, hexane)to provide 3-acetylfuran (2.9 g). The above process was repeated toprovide further material.

c) A mixture of 3-acetylfuran (3.6 g, 27 mmol), hydoxylaminehydrochloride (3.4 g, 50 mmol) and pyridine (5.2 g, 66 mmol) and ethanol(50 mL) was heated at 50° C. for 1 h. The ethanol was evaporated and theresidue was partitioned between ethyl acetate and water. The aqueousphase was extracted with ethyl acetate. The combined organic extract waswashed with 10% HCl and brine, dried over MgSO₄, filtered andconcentrated to give the corresponding oxime (3.4 g) which was used inthe next step.

d) To a solution of the oxime from part c). in ethanol (200 mL) wasadded borane:pyridine complex (8.4 g, 90 mmol) and the mixture wasstirred for 15 min. Then 6N HCl (90 mL) was added dropwise and anexothermic reaction with gas evolution occurred. After about 1 h theethanol was evaporated and the residue was made basic with 2N NaOH. Theaqueous solution was extracted with ethyl acetate twice and the combinedextract was washed with brine, dried over MgSO₄, filtered andconcentrated to give a solid (3.4 g). Purification by chromatography(silica gel, ethyl acetate) gave the desired hydroxylamine intermediate(2.2 g). which was used directly in the next step.

e) To a solution of the hydroxylamine from part d). (2.2 g, 17 mmol) intetrahydrofuran (50 mL) was added dropwise trimethylsilylisocyanate (3.9g, 34 mmol). After stirring at room temperature for 1 h the mixture washeated to reflux for 1 h. After cooling a saturated aqueous solution ofNH₄ Cl was added and the mixture was extracted twice with ethyl acetate.The combined organic extract was washed with brine, dried over MgSO₄,filtered and concentrated to give a white solid. Trituration with etherand filtration gave the desired product (1.9 g). m.p. 128-°130° C.; ¹ HNMR (300 MHz, DMSO-d6) 1.31 (3H, d, J=7.5 Hz), 5.17 (1H, m), 6.35 (2H,bs), 6.39 (1H, m), 7.5 (1H, m), 7.54 (1H, m), 8.98 (1H, s); MS (M+H)⁺=171. Analysis calc'd for C₇ H₁₀ N₂ O₃. C, 49.41; H, 5.92; N, 16.46.Found: C, 49.28; H, 5.97; N, 16.38.

Example 57 N-Hydroxy-N-(1-(5-pyrid-2-ylfur-2-yl)ethyl) urea

a) To a solution of furan (5.0 g, 73 mmol) in tetrahydrofuran (THF, 75mL) at 0° C. was added dropwise a solution of nBuLi (29 mL of 2.5 M inhexane, 73 mmol) and the mixture was stirred for 3 h and thentransferred via a cannula into a stirred solution of anhydrous ZnCl₂(9.9 g, 73 mmol) in THF (75 mL). After stirring for 1 h at roomtemperature this solution was added dropwise via a cannula to a stirredsolution of 2-bromopyridine (7.7 g, 49 mmol) and a catalytic amount ofPd(P(C₆ H₅)₃)₄ (0.28 g, 0.24 mmol) in THF (100 mL). After stirring for24 h, a saturated aqueous solution of NH₄ Cl (10 mL) was added and thesolvent was evaporated. The residue was taken up in water and ether, thelayers were separated and the aqueous phase was extracted with ether.The combined ether extract was washed with brine, dried over MgSO₄,filtered and concentrated to give after purification by chromatography(silica gel, 1:1 ether, hexane) 2-(2 -furyl)pyridine (6.5 g).

b) To a solution of 2-(2-furyl)pyridine (6.5 g, 45 mmol) in ether (250mL) at -78° C. was added a solution of nBuLi (19 mL of 2.5 M in hexane,47 mmol). The mixture was stirred for 1 h at -78° C. and 1,5 h at 0° C.after which as solution of N-methoxy-N-methylacetamide (4.6 g, 45 mmol)in ether (25 mL) was added dropwise and the mixture was stirred for 3days at room temperature. Aqueous NH₄ Cl was added and the layers wereseparated. The aqueous phase was extracted with ethyl acetate and thecombined organic layers were washed with water, brine, dried over MgSO₄,filtered and concentrated to give after purification by chromatography(silica gel, 1:1 ethyl acetate, hexane) 2-(5-acetyl-2- furyl)pyridine(3.5 g).

c) The intermediate from part b) was converted according to the methodof Example 36 parts a)-c) to the desired titled example. m.p. 185°-187°C. (dec); ¹ H NMR (300 MHz, DMSO-d6) 1.43 (3H, d, J=7.5 Hz), 5.39 (1H,m) 6.41 (1H, m), 6.48 (2H, bs), 7.0 (1H, d, J=3.0 Hz), 7.26 (1H, m),7.64 (1H, m), 7.84 (1H, m), 8.55 (1H, m), 9.14 (1H, s); MS (M+H)⁺ =248.Analysis calcd. for C₁₂ H₁₃ N₃ O₃ 1/2H₂ O. C, 56.24; H, 5.51; N, 16.40.Found: C, 56.69; H, 5.27; N, 16.30.

Example 58 N-Hydroxy-N-(fur-2-ylmethyl) urea

The desired product was prepared according to the method of Example 36using 2-furancarboxaldehyde instead of 2- acetylfuran. m.p. 128°-131°C.; ¹ H NMR (300 MHz, DMSO-d6) 4.48 (2H, s), 6.27 (1H, m), 6.4 (3H, m),7.57 (1H, m), 9.39 (1H, s); MS (M+H)⁺ =157. Analysis calc'd for C₆ H₈ N₂O₃. C, 46.15; H, 5.16; N, 17.94. Found: C, 46.38; H, 5.28; N, 17.79.

Example 59 N-hydroxy-N-3-(5-methylfur-2-yl)prop-2-enyl)urea

a) 5-Methylfurfural (10 g, 91 mmol) was added dropwise to 2N NaOH (200mL) and the mixture was stirred for 30 min. A solution of acetaldehyde(8.0 g, 182 mmol) in water (20 mL) was added to the above mixture. Afterstirring for 3 h the mixture was extracted twice with ether and thecombined ether extract was washed with brine, dried over MgSO₄, filteredand concentrated to give after distillation (collected bp 65°-85° C.)3-(5-methylfur-2-yl)-propenal (5.5 g).

b) The aldehyde from part a). was converted according to the method ofexample 36 parts a)-c) to the desired titled compound. m.p. 131°-133°C.; ¹ H NMR (300 MHz, DMSO-d6) 2.28 (3H, s), 4.03 (2H, d, J=7.5 Hz),5.95 (1H, m), 6.07 (1H, m), 6.24 (1H, m), 6.33 (1H, d, J=16 Hz), 6.37(2H, bs), 9.30 (1H, s); MS (M+H)⁺ =197. Analysis calc'd for C₉ H₁₂ N₂O₃. C, 55.09; H, 6.16; N, 14.28. Found: C, 54.77; H, 6.16; N, 14.08.

Example 60 N-hydroxy-N-((1-methyl)-3-(5-methylfur-2-yl)prop-2-enyl) urea

a) To a solution of 5-methylfurfural (2.0 g, 18 mmol) in toluene (50 mL)was added (C₆ H₅)3P=CHCOCH₃ (6.1 g, 19 mmol) and the mixture was stirredat reflux for 18 h. The mixture was cooled and filtered through silicagel and washed with 1:1 ether, hexane. The filtrate was concentrated andpurified by chromatography (silica gel, 40% ether in hexane) to give1-(5-methylfur-2-yl)- buten-3-one.

b) The ketone from part a). was converted according to the method ofexample 36 parts a).-c). to the desired titled compound. m.p. 122°-124°C.; ¹ H NMR (300 MHz, DMSO-d6) 1.19 (3H, d, J=7.5 Hz), 2.26 (3H, s),4.74 (1H, m), 6.01 (1H, m), 6.06 (1H, m), 6.25 (2H, m), 6.36 (2H, m),9.0 (1H, s); MS (M+H)⁺ =211.

The compounds of the following Examples, wherein R₁ =NH₂,A=2--(--CH(CH₃)--), X=O, M=H and Y is as indicated below, can beprepared by methods analogous to those described in Example 2 and bysubstituting the appropriate arylhalide for bromobenzene in step a) ofExample 2.

    ______________________________________                                        Example         Y                                                             ______________________________________                                        61              5-(2-methylpyrid-2-yl)                                        62              5-(pyrid-3-yl)                                                63              5-(pyrid-4-yl)                                                64              5-(2,5-dimethylthien-3-yl)                                    65              5-(5-methylthien-2-yl)                                        66              5-(5-methylfur-2-yl)                                          67              5-(thiazol-2-yl)                                              68              5-(pyrimid-2-yl)                                              69              5-(4-methoxyphenyl)                                           70              5-(4-chlorophenyl)                                            71              5-(4-carbomethoxyphenyl)                                      72              5-(4-cyanophenyl)                                             73              5-(4-fluorophenyl)                                            ______________________________________                                    

The compounds of the following Examples, wherein R₁ =NH₂, A=2--(--CH₂--), X=O, M=H and Y is as indicated below, can be prepared by methodsanalogous to those described in Example 50 and by substituting theappropriate arylhalide for bromobenzene in step a) of Example 50.

    ______________________________________                                        Example         Y                                                             ______________________________________                                        74              5-(pyrid-2-yl)                                                75              5-(pyrid-3-yl)                                                76              5-(pyrid-4-yl)                                                77              5-(2-methylpyrid-3-yl)                                        78              5-(5-methoxypyrid-3-yl)                                       79              5-(N-methylindol-2-yl)                                        80              5-(thiazol-2-yl)                                              81              5-(pyrimid-2-yl)                                              82              5-(4-methoxyphenyl)                                           83              5-(4-chlorophenyl)                                            84              5-(4-carbomethoxyphenyl)                                      85              5-(4-cyanophenyl)                                             86              5-(4-fluorophenyl)                                            ______________________________________                                    

The compounds of the following Examples, wherein R₁ =CH₃,A=2--(--CH(CH₃)--), X=O, M=H and Y is as indicated below, can beprepared by methods analogous to Example 2 and by substituting theappropriate arylhalide for mobenzene in step a) of Example 2. Thisprovides a hydroxylamine which is then converted to the correspondingN-hydroxyacetamide acetamide according to method described in Example 4.

    ______________________________________                                        Example        Y                                                              ______________________________________                                        87             5-(2-methylpyrid-2-yl)                                         88             5-(pyrid-3-yl)                                                 89             5-(pyrid-4-yl)                                                 90             5-(2,5-dimethylthien-3-yl)                                     91             5-(5-methylthien-2-yl)                                         92             5-(5-methylfur-2-yl)                                           93             5-(thiazol-2-yl)                                               94             5-(pyrimid-2-yl)                                               95             5-(4-methoxyphenyl)                                            96             5-(4-chlorophenyl)                                             97             5-(4-carbomethoxyphenyl)                                       98             5-(4-cyanophenyl)                                              99             5-(4-fluorophenyl)                                             ______________________________________                                    

The compounds of the following Examples, wherein R₁ =CH₃, A=2--(--CH₂--), X=O, M=H and Y is as indicated below, can be prepared by methodsanalogous to Example 50 and by substituting the appropriate arylhalidefor bromobenzene in step a) of Example 50. This provides a hydroxylaminewhich is then converted to the corresponding N-hydroxyacetamideacetamide according to method described in Example 4.

    ______________________________________                                        Example        Y                                                              ______________________________________                                        100            5-(pyrid-2-yl)                                                 101            5-(pyrid-3-yl)                                                 102            5-(pyrid-4-yl)                                                 103            5-(2-methylpyrid-3-yl)                                         104            5-(5-methoxypyrid-3-yl)                                        105            5-(indol-2-yl)                                                 106            5-(thiazol-2-yl)                                               107            5-(pyrimid-2-yl)                                               108            5-(4-methoxyphenyl)                                            109            5-(4-chlorophenyl)                                             110            5-(4-carbomethoxyphenyl)                                       111            5-(4-cyanophenyl)                                              112            5-(4-fluorophenyl)                                             ______________________________________                                    

The compounds of the following Examples, wherein R₁ =NH₂,A=2--(--CH(CH₃)--), X=O, M=H and Y is as indicated below, can beprepared by methods analogous to Example 5 and by substituting theappropriate arylmethylphosphonate for diethyl benylphosphonate in stepa) of Example 5.

    ______________________________________                                        Example     Y                                                                 ______________________________________                                        113         5-(--CH═CH-pyrid-2-yl)                                        114         5-(--CH═CH-pyrid-3-yl)                                        115         5-(--CH═CH-pyrid-4-yl)                                        116         5-(CH═CH-5-methylthien-2-yl)                                  117         5-(--CH═CH-2,5-dimethylthien-3-yl)                            118         5-(--CH═CH-5-methylfur-2-yl)                                  119         5-(--CH═CH-2,5-dimethylfur-3-yl)                              120         5-(--CH═CH-3,4,5-trimethoxyphenyl)                            121         5-(--CH═CH-4-methoxyphenyl)                                   122         5-(--CH═CH-4-carbomethoxyphenyl)                              123         5-(--CH═CH-4-cyanophenyl)                                     124         5-(--CH═CH-4-chlorophenyl)                                    125         5-(--CH═CH-4-fluorophenyl)                                    ______________________________________                                    

The compounds of the following Examples, wherein R₁ =NH₂ or CH₃,A=2--(--CH═CH--CH₂ --) or 2--(--CH═CH(CH₃)--), X=O, M=H and Y is asindicated below, can be prepared by methods analogous to those describedin Examples 2, 4, 50, 59 and 60.

    ______________________________________                                        Example        Y                                                              ______________________________________                                        126            5-(pyrid-2-yl)                                                 127            5-(pyrid-3-yl)                                                 128            5-(pyrid-4-yl)                                                 129            5-(2-methylpyrid-3-yl)                                         130            5-(5-methoxypyrid-3-yl)                                        131            5-(N-methylindol-2-yl)                                         132            5-(thiazol-2-yl)                                               133            5-(pyrimid-2-yl)                                               134            5-((4-methoxyphenyl)                                           135            5-(4-chlorophenyl)                                             136            5-(4-carbomethoxyphenyl)                                       137            5-(4-cyanophenyl)                                              138            5-(4-fluorophenyl)                                             ______________________________________                                    

The compounds of the following Examples, wherein R₁ =NH₂,A=2--(--CH(CH)₃ --), X=O, M=H and Y is as indicated below, can beprepared by methods analogous to those described in Example 47.

    ______________________________________                                        Example      Y                                                                ______________________________________                                        139          5-(--CH.sub.2 OCH.sub.2 -pyrid-2-yl)                             140          5-(--CH.sub.2 OCH.sub.2 -pyrid-3-yl)                             141          5-(--CH.sub.2 OCH.sub.2 -pyrid-4-yl)                             142          5-(--CH.sub.2 OCH.sub.2 -(4-methoxyphenyl))                      143          5-(--CH.sub.2 OCH.sub.2 -(4-chlorophenyl))                       144          5-(--CH.sub.2 OCH.sub.2 -(4-carbomethoxy-                                     phenyl))                                                         145          5-(--CH.sub.2 OCH.sub.2 -(4-cyanophenyl))                        146          5-(--CH.sub.2 OCH.sub.2 -(4-fluorophenyl))                       ______________________________________                                    

The compounds of the following Examples, wherein R₁ =NH₂,A=2--(--CH═CH--CH(CH₃)--), X=O, M=H and Y is as indicated below, can beprepared by methods assigned analogous to those described in Example 47and 60.

    ______________________________________                                        Example      Y                                                                ______________________________________                                        147          5-(--CH.sub.2 OCH.sub.2 -pyrid-2-yl)                             148          5-(--CH.sub.2 OCH.sub.2 -pyrid-3-yl)                             149          5-(--CH.sub.2 OCH.sub.2 -pyrid-4-yl)                             150          5-(--CH.sub.2 OCH.sub.2 -(4-methoxyphenyl))                      151          5-(--CH.sub.2 OCH.sub.2 -(4-chlorophenyl))                       152          5-(--CH.sub.2 OCH.sub.2 -(4-carbomethoxy-                                     phenyl))                                                         153          5-(--CH.sub.2 OCH.sub.2 -(4-cyanophenyl))                        154          5-(--CH.sub.2 OCH.sub.2 -(4-fluorophenyl))                       ______________________________________                                    

The compounds of the following Examples, wherein R₁ =NH₂,A=2--(--CH(CH₃)--), X=NR₄ wherein R₄ is indicated below, M=H and Y is asindicated below, can be prepared by methods analogous to those describedin Example 8.

    ______________________________________                                        Example    Y               R.sub.4                                            ______________________________________                                        155        5-(4-fluorophenyl)                                                                            --CH.sub.2 -(4-chloro-                                                        phenyl)                                            156        5-(pyrid-3-yl)  --CH.sub.2 -(4-chloro-                                                        phenyl)                                            157        5-(pyrid-4-yl)  --CH.sub.2 -(4-chloro-                                                        phenyl)                                            158        5-(pyrid-2-yl)  methyl                                             159        5-(4-chlorophenyl)                                                                            methyl                                             160        5-(4-carbomethoxy-                                                                            methyl                                                        phenyl)                                                            161        5-(4-chlorophenyl)                                                                            --CH.sub.2 -pyrid-4-yl                             ______________________________________                                    

Inhibition of 5-Lipoxygenase

Inhibition of 5-lipoxygenase activity was determined using the 20,000× gsupernatant from homogenized RBL-1 cells in a similar manner to thatdescribed by Dyer and coworkers (Dyer, R. D.; Haviv, F.; Hanel, A. M.;Bornemier, D. A.; Carter, G. W. Fed. Proc., Fed. Am. Soc. Exp. Biol.1984, 43, 1462A). Inhibitory potencies for representative examples ofthis invention are listed in Table 1. IC₅₀ values (concentration ofcompound producing 50% enzyme inhibition) were calculated by linearregression analysis of percentage inhibition versus log inhibitorconcentration plots.

                  TABLE 1                                                         ______________________________________                                        In vitro 5-lipoxygenase inhibitory potency of                                 representative compounds of this invention.                                          Example                                                                              IC.sub.50 (uM)                                                  ______________________________________                                               1      12                                                                     2      0.54                                                                   3      0.70                                                                   4      0.51                                                                   5      0.30                                                                   6      0.33                                                                   7      18                                                                     9      14                                                                     10     19                                                                     11     24                                                                     12     0.3                                                                    13     1.2                                                                    36     24                                                                     37     11                                                                     39     0.9                                                                    40     0.4                                                                    41     3.5                                                                    43     13                                                                     49     1.1                                                                    50     0.45                                                                   51     1.3                                                                    52     4.5                                                                    53     0.19                                                                   54     4.0                                                                    55     2.9                                                                    56     15                                                                     57     6.4                                                                    59     2.0                                                                    60     1.2                                                             ______________________________________                                    

The results of the assay indicate that the compounds are inhibitors of5-lipoxygenase.

Inhibition of Leukotriene Biosynthesis

Inhibition of the biosynthesis of leukotrienes in vivo afterintraperitoneal administration of compound was determined using a ratperitoneal anaphylaxis model. In this model rats were injectedintraperitoneally (ip) with rabbit antibody to bovine serum albumin(BSA) and three hours later injected i.p. with BSA to induce anantigen-antibody response. Rats were sacrificed 15 minutes after thischallenge and the peritoneal fluids were collected and analyzed forleukotriene levels. Test compound was administered by oral gavage onehour prior to the antigen challenge. Percent inhibition values weredetermined by comparing the treatment group to the mean of the controlgroup. From the results of this assay it is demonstrated that compoundsof this invention are orally effective in preventing the in vivobiosynthesis of leukotrienes. The results for representative examples ofthis invention are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        In vivo inhibition of leukotriene biosynthesis by                             representative compounds of this invention.                                               % Inhibition with                                                 Example     200 umol/kg Oral Dose                                             ______________________________________                                        1           84                                                                2           96                                                                3           92                                                                4           87                                                                5           89                                                                6           81                                                                9           91                                                                11          90                                                                12          91                                                                36          57                                                                43          49                                                                49          98                                                                50          78                                                                52          92                                                                53          89                                                                55          66                                                                56          78                                                                57          75                                                                59          94                                                                ______________________________________                                    

the foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope of and nature of the invention which are defined inthe appended claims.

What is claimed is:
 1. A compound of the formula ##STR8## wherein R₁ isselected fromC₂ to C₄ alkyl, C₂ to C₄ alkenyl, and --NR₂ R₃ where R₂ andR₃ are independently selected fromhydrogen, C₁ to C₄ alkyl, hydroxyl,and an aryl group selected from substituted or unsubstitutedphenyl, 1-or 2-naphthyl, and fluorenyl; the substituents selected fromhalo, nitro,cyano, C₁ to C₄ alkyl, alkoxy, halosubstituted alkyl, alkoxycarbonyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, andalkylsulfonyl; with the proviso that R₂ and R₃ are not both hydroxyl; Xis oxygen or NR₄ wherein R₄ is selected fromhydrogen, C₁ to C₆ alkyl, C₁to C₆ alkoxyl, arylalkyl wherein the aryl portion is as defined above; Ais selected from C₁ to C₆ alkylene ands C₂ to C₆ alkenylene; n is 0, 1,2, or 3; Y is selected independently at each occurrence fromhydrogen,halogen, hydroxy, cyano, halosubstituted alkyl, C₁ to C₁₂ alkyl, C₂ toC₁₂ alkenyl, C₁ to C₁₂ alkoxyl, C₃ to C₈ cycloalkyl, aryl as definedabove, aryloxy wherein the aryl portion is as defined above, aroyl asdefined above; C₁ to C₁₂ arylalkyl wherein the aryl portion is asdefined above, C₁ to C₁₂ arylalkoxy wherein the aryl portion is asdefined above, C₁ to C₁₂ arylthioalkoxy wherein the aryl portion is asdefined above, alkoxycarbonyl, arylalkoxycarbonyl wherein the arylportion is as defined above, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylalkylamino or wherein the aryl portion is asdefined above, alkoxyalkoxyalkyl, arylalkoxyalkyl wherein the arylportion is as defined above, arylthioalkoxyalkyl wherein the arylportion is as defined above, substituted aryl, aryloxy, aroyl,arylalkyl, arylalkenyl, arylalkoxy, arylthioalkoxy, arylalkoxyalkyl, orarylthioalkoxyalkyl, as defined above,wherein the substituents areselected fromhalo, nitro, cyano, C₁ to C₁₂ alkyl, alkoxy, andhalosubstituted alkyl; the groups(s) Y may be substituted from any ofthe positions on the ring; and M is hydrogen, a pharmaceuticallyacceptable cation, aroyl as defined above, or C₁ to C₁₂ alkoyl.
 2. Thecompound of claim 1 wherein R₁ is --CH₃ or --NH₂ and X is oxygen.
 3. Thecompound of claim 1 wherein R₁ is --CH₃ or --NH₂ and X is NR₄ wherein R₄is hydrogen, C₁ to C₆ alkyl, C₁ to C₆ alkoxl, arylalkyl or aroyl asdefined therein.
 4. The compound of claim 1 wherein A is --CH(CH₃)--,--CH₂ --, --CH═CH--CH₂ -- or --CH═CH--CH(CH₃)--.
 5. A compound selectedfrom:N-hydroxy-N-(1-(5-methylfur-2-yl)ethyl) urea;N-hydroxy-N-(1-(5-phenylfur-2-yl)ethyl) urea;N-hydroxy-N-(1-(5-phenylfur-2-yl)ethyl)-N'-methyl urea;N-hydroxy-N-(1-(5-phenylfur-2-yl)ethyl) acetamide;N-hydroxy-N-(1-(5-(2-phenylethenyl)fur-2-yl)ethyl) urea;N-hydroxy-N-(1-(5-(2-phenylethenyl)fur-2-yl)ethyl)-N'-methyl urea;N-hydroxy-N-(5-(2,4,6-trimethoxyphenyl)-fur-2-ylethyl) urea;N-hydroxy-N-(1-(5-benzyloxymethylfur-2-yl)ethyl) urea;N-hydroxy-N-(5-phenylfur-2-ylmethyl) urea;N-hydroxy-N-(3-fur-3-ylprop-2-enyl) ureaN-hydroxy-N-(3-(5-phenylfur-2-yl)prop-2-enyl) urea; N-hydroxy-N-(1-fur3-ylethyl) urea; N-hydroxy-N-3-(1-(5-methylfur-2-yl)propenyl) urea; andN-hydroxy-N-((1-methyl)-3-(5-methylfur-2-yl)prop-2-enyl) urea. 6.N-hydroxy-N-(1-fur-3-ylethyl) urea.
 7. A method for inhibiting 5- and/or12-lipoxygenase activity or inhibiting leukotriene biosynthesiscomprising administering to a mammal in need of such treatment atherapeutically effective amount of a compound of claim
 1. 8. A methodfor inhibiting 5- and/or 12-lipoxygenase activity or inhibitingleukotriene biosynthesis comprising administering to a mammal in need ofsuch treatment a therapeutically effective amount ofN-hydroxy-N-(1-fur-3-ylethyl) urea.
 9. A pharmaceutical composition forinhibiting 5- and/or 12- lipoxygenase or inhibiting leukotrienebiosynthesis, comprising a pharmaceutical carrier and a therapeuticallyeffective amount of a compound of claim
 1. 10. A pharmaceuticalcomposition for inhibiting 5- and/or 12- lipoxygenase or inhibitingleukotriene biosynthesis, comprising a pharmaceutical carrier and atherapeutically effective amount of N-hydroxy-N-(1-fur-3-ylethyl) urea.